Compositions and methods for inhibition of the jak pathway

ABSTRACT

The invention encompasses compounds having formula I-V and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3, may be therapeutically useful.

I. CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 13/750,632,filed Jan. 25, 2013, which is a divisional of U.S. patent applicationSer. No. 12/193,627, filed Aug. 18, 2008, now U.S. Pat. No. 8,399,472,which is a continuation of U.S. patent application Ser. No. 11/450,901,filed Jun. 8, 2006, now U.S. Pat. No. 7,491,732, which claims thebenefit of U.S. provisional application No. 60/689,032, filed Jun. 8,2005, U.S. provisional application No. 60/706,638, filed Aug. 8, 2005,and U.S. Provisional application No. 60/776,636, filed Feb. 24, 2006.

II. INTRODUCTION

A. Field

The present disclosure relates to compounds, prodrugs, and methods ofusing these compounds and prodrugs thereof in the treatment ofconditions in which modulation of the JAK pathway or inhibition of JAKkinases, particularly JAK3, may be therapeutically useful.

B. Background

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within cells (see e.g., Hardie and Hanks, TheProtein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.,1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these families (see,e.g., Hanks & Hunter, (1995), FASEB J. 9:576-596; Knighton et al.,(1991), Science 253:407-414; Hiles et al., (1992), Cell 70:419-429; Kunzet al., (1993), Cell 73:585-596; Garcia-Bustos et al., (1994), EMBO J.13:2352-2361).

JAK kinases (JAnus Kinases) are a family of cytoplasmic protein tyrosinekinases including JAK1, JAK2, JAK3 and TYK2. Each of the JAK kinases isselective for the receptors of certain cytokines, though multiple JAKkinases may be affected by particular cytokine or signaling pathways.Studies suggest that JAK3 associates with the common gamma (γc) chain ofthe various cytokine receptors. JAK3 in particular selectively binds toreceptors and is part of the cytokine signaling pathway for IL-2, IL-4,IL-7, IL-9, IL-15 and IL-21. JAK1 interacts with, among others, thereceptors for cytokines IL-2, IL-4, IL-7, IL-9 and IL-21, while JAK2interacts with, among others, the receptors for IL-9 and TNF-α. Uponbinding of certain cytokines to their receptors (e.g., IL-2, IL-4, IL-7,IL-9, IL-15 and IL-21), receptor oligomerization occurs, resulting inthe cytoplasmic tails of associated JAK kinases being brought intoproximity and facilitating the trans-phosphorylation of tyrosineresidues on the JAK kinase. This trans-phosphorylation results in theactivation of the JAK kinase.

Phosphorylated JAK kinases bind various STAT (Signal Transducer andActivator of Transcription) proteins. STAT proteins, which are DNAbinding proteins activated by phosphorylation of tyrosine residues,function both as signaling molecules and transcription factors andultimately bind to specific DNA sequences present in the promoters ofcytokine-responsive genes (Leonard et al., (2000), J. Allergy Clin.Immunol. 105:877-888). JAK/STAT signaling has been implicated in themediation of many abnormal immune responses such as allergies, asthma,autoimmune diseases such as transplant (allograft) rejection, rheumatoidarthritis, amyotrophic lateral sclerosis and multiple sclerosis, as wellas in solid and hematologic malignancies such as leukemia and lymphomas.For a review of the pharmaceutical intervention of the JAK/STAT pathwaysee Frank, (1999), Mol. Med. 5:432:456 and Seidel et al., (2000),Oncogene 19:2645-2656.

JAK3 in particular has been implicated in a variety of biologicalprocesses. For example, the proliferation and survival of murine mastcells induced by IL-4 and IL-9 have been shown to be dependent on JAK3-and gamma chain-signaling (Suzuki et al., (2000), Blood 96:2172-2180).JAK3 also plays a crucial role in IgE receptor-mediated mast celldegranulation responses (Malaviya et al., (1999), Biochem. Biophys. Res.Commun. 257:807-813), and inhibition of JAK3 kinase has been shown toprevent type I hypersensitivity reactions, including anaphylaxis(Malaviya et al., (1999), J. Biol. Chem. 274:27028-27038). JAK3inhibition has also been shown to result in immune suppression forallograft rejection (Kirken, (2001), Transpl. Proc. 33:3268-3270). JAK3kinases have also been implicated in the mechanism involved in early andlate stages of rheumatoid arthritis (Muller-Ladner et al., (2000), J.Immunal. 164:3894-3901); familial amyotrophic lateral sclerosis (Trieuet al., (2000), Biochem Biophys. Res. Commun. 267:22-25); leukemia(Sudbeck et al., (1999), Clin. Cancer Res. 5:1569-1582); mycosisfungoides, a form of T-cell lymphoma (Nielsen et al., (1997), Prac.Natl. Acad. Sci. USA 94:6764-6769); and abnormal cell growth (Yu et al.,(1997), J. Immunol. 159:5206-5210; Catlett-Falcone et al., (1999),Immunity 10:105-115).

The JAK kinases, including JAK3, are abundantly expressed in primaryleukemic cells from children with acute lymphoblastic leukemia, the mostcommon form of childhood cancer, and studies have correlated STATactivation in certain cells with signals regulating apoptosis (Demoulinet al., (1996), Mol. Cell. Biol. 16:4710-6; Jurlander et al., (1997),Blood. 89:4146-52; Kaneko et al., (1997), Clin. Exp. Immun. 109:185-193;and Nakamura et al., (1996), J. Biol. Chem. 271:19483-8). They are alsoknown to be important to lymphocyte differentiation, function andsurvival. JAK-3 in particular plays an essential role in the function oflymphocytes, macrophages, and mast cells. Given the importance of thisJAK kinase, compounds which modulate the JAK pathway, including thoseselective for JAK3, can be useful for treating diseases or conditionswhere the function of lymphocytes, macrophages, or mast cells isinvolved (Kudlacz et al., (2004) Am. J. Transplant 4:51-57; Changelian(2003) Science 302:875-878). Conditions in which targeting of the JAKpathway or modulation of the JAK kinases, particularly JAK3, may betherapeutically useful include, leukemia, lymphoma, transplant rejection(e.g. pancreas islet transplant rejection, bone marrow transplantapplications (e.g. graft-versus-host disease), autoimmune diseases (e.g.diabetes), and inflammation (e.g. asthma, allergic reactions).Conditions which may benefit from inhibition of JAK3 are discussed ingreater detail below.

In view of the numerous conditions that may benefit by treatmentinvolving modulation of the JAK pathway, it is immediately apparent thatnew compounds that modulate JAK pathways and methods of using thesecompounds should provide substantial therapeutic benefit to a widevariety of patients. Provided herein are novel 2,4-substitutedpyrimidinediamine compounds for use in the treatment of conditions inwhich targeting of the JAK pathway or inhibition of JAK kinases,particularly JAK3, may be therapeutically useful.

Patents and patent applications related to modulation of the JAK pathwayinclude: U.S. Pat. Nos. 5,728,536; 6,080,747; 6,080,748; 6,133,305;6,177,433; 6,210,654; 6,313,130; 6,316,635; 6,433,018; 6,486,185;6,506,763; 6,528,509; 6,593,357; 6,608,048; 6,610,688; 6,635,651;6,677,368; 6,683,082; 6,696,448; 6,699,865; 6,777,417; 6,784,195;6,825,190; U.S. Pat. App. Pub. No. 2001/0007033 A1; 2002/0026053 A1;2002/0115173 A1; 2002/0137141 A1; 2002/0151574 A1; 2003/0040536 A1;2003/0065180 A1; 2003/0069430 A1; 2003/0225151 A1; 2003/0236244 A1;2004/0009996 A1; 2004/0072836 A1; 2004/0082631 A1; 2004/0102455 A1;2004/0102506 A1; 2004/0127453 A1; 2004/0142404 A1; 2004/0147507 A1;2004/0186157 A1; 2004/0205835 A1; and 2004/0214817 A1; and Internationalpatent applications WO 95/03701A1; WO 99/15500A1; WO 00/00202A1; WO00/10981A1; WO 00/47583A1; WO 00/51587A2; WO 00/55159A2; WO 01/42246A2;WO 01/45641A2; WO 01/52892A2; WO 01/56993A2; WO 01/57022A2; WO01/72758A1; WO 02/00661A1; WO 02/43735A1; WO 02/48336A2; WO 02/060492A1;WO 02/060927A1; WO 02/096909A1; WO 02/102800A1; WO 03/020698A2; WO03/048162A1; WO 03/101989A1; WO 04/016597A2; WO 04/041789A1; WO04/041810A1; WO 04/041814A1; WO 04/046112A2; WO 04/046120A2; WO04/047843A1; WO 04/058749A1; WO 04/058753A1; WO 04/085388A2; WO04/092154A1; WO 05/009957A1; WO 05/016344A1; WO 05/028475A2; and WO05/033107A1.

Patents and patent applications describing substituted pyrimidinediaminecompounds include: U.S. Pat. App. Pub. No. 2004/0029902 A1; 2005/0234049A1, and published International applications WO 03/063794, WO 04/014382,and WO 05/016893, the disclosures of which are incorporated herein byreference. Substituted pyrimidinediamine compounds are also described ininternational patent application publication numbers: WO 02/059110, WO03/074515, WO 03/106416, WO 03/066601, WO 03/063794, WO 04/046118, WO05/016894, WO 05/0122294, WO 05/066156, WO 03/002542, WO 03/030909, WO00/039101, WO 05/037800 and U.S. Pat. Pub. No. 2003/0149064.

All of the above publications are herein incorporated by reference intheir entirety to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by referencein its entirety.

III. SUMMARY OF THE INVENTION

This invention is directed to compounds, prodrugs, and methods of usingthese compounds and prodrugs thereof in the treatment of conditions inwhich modulation of the JAK pathway or inhibition of JAK kinases,particularly JAK3, may be therapeutically useful.

One embodiment of the invention provides compounds or solvates, prodrugsor pharmaceutically acceptable salts of compounds of formula I:

wherein:

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   R is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl and substituted cycloalkyl;    -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   Y is selected from the group consisting of a bond, —NR⁷—,        —C(O)NR⁷—, —NR⁷C(O)—,    -   —NR⁷C(O)O—, —OC(O)NR⁷—, —NR⁷C(O)NR⁷—, oxygen and sulfur, where        R⁷ is independently hydrogen, alkyl or substituted alkyl;    -   alk is a bond or a straight or branched chain alkylene group,        wherein when alk and Y each are a bond then R¹ is attached to        ring A by a single covalent bond;    -   R¹ is selected from the group consisting of cyano, acylamino,        aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester,        carboxyl ester oxy, heteroaryl, substituted heteroaryl,        heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and        aminocarbonylamino; or        -   R¹-alk-Y— is R¹⁰—C(O)—S-alk-C(O)—, wherein alk is as defined            herein and R¹⁰ is alkyl or substituted alkyl; or        -   R¹-alk-Y— is R¹¹R¹²NS(O)₂—, wherein R¹¹ and R¹²            independently are alkyl or substituted alkyl;    -   p is 0, 1, 2 or 3 when ring A is a single ring or p is 0, 1, 2,        3, 4, or 5 when ring A comprises multiple rings;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro, and halo, or two of R² on the        same carno form an oxo (═O);    -   Z¹, Z², and Z³ each independently is carbon or nitrogen, wherein        if Z¹ is nitrogen then Z² and Z³ are carbon, if Z² is nitrogen        then Z¹ and Z³ are carbon, and if Z³ is nitrogen then Z¹ and Z²        are carbon, wherein if Z¹, Z², or Z³ is nitrogen then SO₂R⁴R⁵ is        not attached to the nitrogen;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺ N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO₂NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group; or        -   when q is 1, 2 or 3, R⁵ can be joined with one R³ group            bound alpha thereto, to form a fused ring as illustrated in            formula II:

-   -   -   wherein W is selected from the group consisting of C₁-C₃            alkylene, substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and            substituted C₂-C₃ alkenylene wherein one or more of the            carbon atoms have been replaced with a moiety selected from            oxygen, sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is            selected from the group consisting of hydrogen and alkyl or            is a bond participating in a —N═C< site of unsaturation;            provided that:

    -   when alk is a bond and Y is a bond, then R¹ is not cyano,        carboxyl, carboxyl ester, or aminoacarbonylamino;

    -   when alk is —CH₂—, Y is oxygen and R¹ is phenyl, ring A is not        cycloalkyl;

    -   when alk is a bond, Y is a bond, ring A is phenyl, then R¹ is        not heterocyclic, substituted heterocyclic or aminoacyloxy;

    -   when Y or R¹-alk-Y— provide for direct linkage of either        —NR⁷C(O)O— or —NR⁷C(O)NR⁷— to ring A, then R⁷ is hydrogen; and

    -   when Y is —C(O)NR⁷—, —NR⁷C(O)—, —OC(O)NR⁷—, —NR⁷C(O)O— or        —NR⁷C(O)NR⁷— and alk is a bond, then R¹ is not acyl, acylamino,        aminoacyl or aminocarbonylamino.

Another embodiment of the invention provides compounds, or solvates,prodrugs of pharmaceutical acceptable salts of compounds of formula III:

where:

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   R is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl and substituted cycloalkyl;    -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, sulfonyl, oxo, nitro and halo;    -   Z¹, Z², and Z³ each independently is carbon or nitrogen, wherein        if Z¹ is nitrogen then Z² and Z³ are carbon, if Z² is nitrogen        then Z¹ and Z³ are carbon, and if Z³ is nitrogen then Z¹ and Z²        are carbon, wherein if Z¹, Z², or Z³ is nitrogen then SO₂R⁴R⁵ is        not attached to the nitrogen;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group; or        -   when q is 1, 2 or 3, R⁵ can be joined with one R³ group            bound alpha thereto, to form a fused ring as illustrated in            formula IV:

-   -   -   wherein W is selected from the group consisting of C₁-C₃            alkylene, substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and            substituted C₂-C₃ alkenylene wherein one or more of the            carbon atoms have been replaced with a moiety selected from            oxygen, sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is            selected from the group consisting of hydrogen and alkyl or            is a bond participating in a —N═C< site of unsaturation;            provided that:

    -   if p=0, then X is not bromo;

    -   if ring A is cycloalkyl, then X is not bromo;

    -   if p=2 and each of R² is methoxy, halo, trihalomethyl or        trihalomethoxy, then R⁴ and R⁵ are not one hydrogen and one        methyl;

    -   if p=2 and R² is fluoro and methyl, then R is not substituted        alkenyl; and

    -   if ring A is phenyl, p=1 and R² is chloro, then R⁴ and R⁵ are        not one hydrogen and one methyl.

Yet another embodiment of the invention provides a compound selectedfrom the group consisting of:

cmpd name I-1N2-(4-Aminosulphonylphenyl)-N4-(3-cyanomethoxy-4,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-2N2-(3-Aminosulphonyl-4-methylphenyl)-N4-(3-cyanomethoxy-4,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-3N2-(4-Aminosulfonyl)phenyl-N4-(3-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-4N2-(3-Aminosulfonyl)phenyl-N4-(3-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-5N4-(3-Cyanomethoxy)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine;I-6N4-(3-Cyanomethoxy)phenyl-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine;I-7N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-(3-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-8N2-(3-Aminosulfonyl-4-iso-propylphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-9N2-[3-Aminosulfonyl-4-(4-methylpiperazin-1-yl)phenyl]-5-fluoro-N4-(4-cyanomethyleneoxyphenyl)-2,4-pyrimidinediamine;I-10N2-[3-Aminosulfonyl-4-(4-methylpiperazine-1-yl)phenyl]-5-fluoro-N4-(4-cyanomethyleneoxy-3-fluorophenyl)-2,4-pyrimidinediamine;I-11N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-cyanomethyleneoxy-3-fluorophenyl)-2,4-pyrimidinediamine;I-12N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-cyanomethyleneoxy-3-fluorophenyl)-2,4-pyrimidinediamine;I-13N2-(3-Aminosulfonylphenyl)-5-bromo-N4-(4-cyanomethyleneoxyphenyl)-2,4-pyrimidinediamine;I-14N2-(3-Aminosulfonyl-4-methylphenyl)-5-bromo-N4-(4-cyanomethyleneoxyphenyl)-2,4-pyrimidinediamine;I-15N2-(3-Aminosulfonylphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-trimethylsilylacetylene-2,4-pyrimidinediamine;I-16N2-(4-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-17N2-(3-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-18N4-(4-Cyanomethoxy)phenyl-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine;I-19N4-(4-Cyanomethoxy)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine;I-20N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-21N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-22N2-(4-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-23N2-(3-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-24N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-25N2-(4-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-26N2-(3-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-27N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-28N2-(4-Aminosulfonyl-3-methoxyphenyl)-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-29N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-30N4-(4-Cyanomethyleneoxy)phenyl-5-fluoro-N2-(4-methyl-3-propionylaminosulfonyl)phenyl-2,4-pyrimidinediamine(68); I-31N4-(4-Cyanomethyleneoxy)phenyl-5-fluoro-N2-(4-methyl-3-propionylaminosulfonyl)phenyl-2,4-pyrimidinediaminesodium salt (69); I-32N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-33N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-34N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-35N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-36N2-(3-Acetylaminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;I-37N4-(4-Cyanomethyleneoxy)phenyl-5-fluoro-N2-(3-isobutyrylaminosulfonyl-4-methyl)phenyl-2,4-pyrimidinediamine;I-38N2-(3-Acetylaminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediaminesodium salt; I-39N4-(4-Cyanomethyleneoxy)phenyl-5-fluoro-N2-(3-isobutyrylaminosulfonyl-4-methyl)phenyl-2,4-pyrimidinediaminesodium Salt; I-40N4-(4-Cyanomethoxy-3,5-dimethylphenyl)-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]-2,4-pyrimidinediamine;I-41N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-cyanomethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-42N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-cyanomethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-43N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-cyanomethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-44N2-(4-Aminosulfonylphenyl)-N4-(4-cyanomethoxy-3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine;I-45N2-(4-Aminosulfonylphenyl)-N4-(4-cyanomethoxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-46N2-(3-Aminosulfonylphenyl)-N4-(4-cyanomethoxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-47N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanomethoxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-48N4-(4-Cyanomethoxy-3-fluorophenyl)-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine;I-49N4-(4-Cyanomethoxy-3-fluorophenyl)-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamineSodium Salt; I-50N2-(3-Aminosulfonylphenyl)-N4-(4-cyanomethoxy-3-hydroxymethylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-51N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanomethoxy-3-hydroxymethylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-52N2-(4-Aminosulfonylphenyl)-N4-[4-cyanomethoxy-3-(1-cyanomethylpyrazol-3-yl)phenyl]-5-fluoro-2,4-pyrimidinediamine;I-53N2-(3-Aminosulfonylphenyl)-N4-[4-cyanomethoxy-3-(1-cyanomethylpyrazol-3-yl)phenyl]-5-fluoro-2,4-pyrimidinediamine;I-54N2-(3-Aminosulfonyl-4-methylphenyl]-N4-[4-cyanomethoxy-3-(1-cyanomethylpyrazol-3-yl)phenyl]-5-fluoro-2,4-pyrimidinediamine;I-55N2-(3-Aminosulfonylpyrid-4-yl)-N4-(4-cyanomethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-56N2-(3-Aminosulfonyl-4-methoxyphenyl)-N4-(4-cyanomethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-57N2-(4-Aminosulfonylphenyl)-N4-(4-cyanomethoxyphenyl-5)-methyl-2,4-pyrimidinediamine;I-58N2-(3-Aminosulfonylphenyl)-N4-(4-cyanomethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-59N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanomethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-60 RacemicN2-(4-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine;I-61 RacemicN2-(3-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine;I-62 RacemicN2-(3-Aminosulfonyl-4-methyl)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine;I-63 RacemicN2-(4-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy-3,5-dimethyl]phenyl-5-fluoro-2,4-pyrimidinediamine;I-64 RacemicN2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine;I-65 RacemicN2-(3-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-66 RacemicN2-(4-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-67 RacemicN2-(3-Aminosulfonyl-4-methyl)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-68 RacemicN2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-69 RacemicN2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine;I-70 RacemicN2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-71 RacemicN2-(3-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy-3,5-dimethyl]phenyl-5-fluoro-2,4-pyrimidinediamine;I-72 RacemicN2-(3-Aminosulfonyl-4-methyl)phenyl-N4-[4-(1-cyano)ethoxy-3,5-dimethyl]phenyl-5-fluoro-2,4-pyrimidinediamine;I-73N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-74N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-75N2-(4-Aminosulfonyl)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-76N2-(3-Aminosulfonyl)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-77N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine;I-78N2-(3-Aminosulfonylphenyl)-N4-[4-(N-cyanoacetyl)aminophneyl]-5-fluoro-2,4-pyrimidinediamine.I-79N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(N-cyanoacetyl)aminophneyl]-5-fluoro-2,4-pyrimidinediamine;I-80N2-(3-Aminosulfonylphenyl)-5-fluoroN4-[3-methyl-4-(N-cyanoacetyl)aminophneyl]-2,4-pyrimidinediamine;I-81N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoroN4-[3-methyl4-(N-cyanoacetyl)aminophneyl]-2,4-pyrimidinediamine;I-82N2-(3-Aminosulfonylphenyl)-N4-[3-chloro-4-(N-cyanoacetyl)aminophneyl]-5-fluoro-2,4-pyrimidinediamine;I-83N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-chloro-4-(N-cyanoacetyl)aminophneyl]-5-fluoro-2,4-pyrimidinediamine;I-84N2-(3-Aminosulfonylphenyl)-5-fluoroN4-[3-methoxy-4-(N-cyanoacetyl)aminophneyl]-2,4-pyrimidinediamine;I-85N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoroN4-[3-methoxy-4-(N-cyanoacetyl)aminophneyl]-2,4-pyrimidinediamine;I-86N2-(3-Aminosulfonylphenyl)-N4-[4-(N-cyanoacetyl-N-methyl)aminophneyl]-5-fluoro-2,4-pyrimidinediamine;I-87N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(N-cyanoacetyl-N-methyl)aminophneyl]-5-fluoro-2,4-pyrimidinediamine;I-88N4-(3-Aminocarbonylmethoxy)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-89N4-(3-Aminocarbonylmethoxy)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine;I-90N4-(3-Aminocarbonylmethoxy)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-91N4-(3-Aminocarbonylmethoxy)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-92N4-(4-Aminocarbonylmethoxy-3-methyl)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-93N4-(4-Aminocarbonylmethoxy-3,5-dimethyl)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-94N4-(4-Aminocarbonylmethoxy)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-95N4-(4-Aminocarbonylmethoxy-3-methyl)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-96N4-(4-Aminocarbonylmethoxy-3,5-dimethyl)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-97N4-(4-Aminocarbonylmethoxy-3-chlorophenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-98N4-(4-Aminocarbonylmethoxy-3-chlorophenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-99N4-(4-Aminocarbonylmethoxy-3-chlorophenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-100N4-(4-Aminocarbonylmethoxy-3-fluorophenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-101N4-(4-Aminocarbonylmethoxy-3-fluorophenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-102N4-(4-Aminocarbonylmethoxy-3-fluorophenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-103N4-(4-Aminocarbonylmethoxy-3-methoxyphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-104N4-(4-Aminocarbonylmethoxy-3-methoxyphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-105N4-(4-Aminocarbonylmethoxy-3-methoxyphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-106N4-(4-Aminocarbonylmethoxy-3-hydroxymethylphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-107N4-(4-Aminocarbonylmethoxy-3-hydroxymethylphenyl]-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-108N4-(4-Aminocarbonylmethoxyphenyl)-N2-(4-aminosulfonylphenyl)-5-methyl-2,4-pyrimidinediamine;I-109N4-(4-Aminocarbonylmethoxyphenyl)-N2-(3-aminosulfonylphenyl)-5-methyl-2,4-pyrimidinediamine;I-110N4-(4-Aminocarbonylmethoxyphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-methyl-2,4-pyrimidinediamine;I-111N4-(4-Aminocarbonylmethoxy)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-112N4-(4-Aminocarbonylmethoxy)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine;I-113N4-(4-Aminocarbonylmethoxy-3-methyl)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-114N4-(4-Aminocarbonylmethoxy-3,5-dimethyl)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-115N4-(4-Aminocarbonylmethoxy)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-116 RacemicN4-[4-(1-Aminocarbonyl)ethoxy]phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-117 RacemicN4-[4-(1-Aminocarbonyl)ethoxy]phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-118N4-[4-(1-Aminocarbonyl)ethoxy]phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-119 RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3-methyl]phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-120 RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3-methyl]phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-121 RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3-methyl]phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-122 RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3,5-dimethyl]phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-123 RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3,5-dimethyl]phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-124 RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3,5-dimethyl]phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-125N4-[4-(1-Aminocarbonyl-1-methyl)ethoxy]phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-126N4-[4-(1-Aminocarbonyl-1-methyl)ethoxy]phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-127N4-[4-(1-Aminocarbonyl-1-methyl)ethoxy]phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;I-128N2-(4-Aminosulfonylphenyl)-N4-(4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-129N2-(3-Aminosulfonylphenyl)-N4-(4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-130N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-131N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-132N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-133N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-134N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-135N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-136N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-137N2-(4-Aminosulfonylphenyl)-N4-(4-dimethylaminocarbonylmethoxy-3-fluorophenyl)-5-methyl-2,4-pyrimidinediamine;I-138N2-(3-Aminosulfonylphenyl)-N4-(4-dimethylaminocarbonylmethoxy-3-fluorophenyl)-5-methyl-2,4-pyrimidinediamine;I-139N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-dimethylaminocarbonylmethoxy-3-fluorophenyl)-5-methyl-2,4-pyrimidinediamine;I-140N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-141N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-142N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(4-dimethylaminocarbonylmethoxy-3-fluorophenyl)-5-methyl-2,4-pyrimidinediamine;I-143N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethoxyphenyl)-2,4-pyrimidinediamine;I-144N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethoxyphenyl)-2,4-pyrimidinediamine;I-145N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethoxyphenyl)-2,4-pyrimidinediamine;I-146N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-147N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-148N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-149N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-150N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-151N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-152N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;I-153N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-154N2-(4-Aminosulfonylphenyl)-N4-(3-fluoro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-155N2-(3-Aminosulfonylphenyl)-N4-(3-fluoro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-156N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-fluoro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;I-157N4-(4-Allylaminocarbonylmethoxyphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-158N4-(4-Allylaminocarbonylmethoxyphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-159N4-(4-Allylaminocarbonylmethoxyphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;I-160N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-1615-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-162N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-163N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-164N2-(3-Aminosulfonylpyrid-4-yl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-165N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-166N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-167N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[(4-((pyridin-2-yl)methoxy)-3-methylphenyl)]-2,4-pyrimidinediamine;I-168N2-(3-Amino-4-methylsulfonylphenyl)-5-fluoro-N4-[(4-((pyridin-2-yl)methoxy)-3-methylphenyl)]-2,4-pyrimidinediamine;I-169N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-fluoromethyleneoxyphenyl]-2,4-pyrimidinediamine;I-1705-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(2-pyridinyl)-3-methylmethyleneoxyphenyl]-2,4-pyrimidinediamine;I-171N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-chloromethyleneoxyphenyl]-2,4-pyrimidinediamine;I-172N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-fluoromethyleneoxyphenyl]-2,4-pyrimidinediamine;I-1735-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(2-pyridinyl)-3-fluoromethyleneoxyphenyl]-2,4-pyrimidinediamine;I-174N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-chloromethyleneoxyphenyl]-2,4-pyrimidinediamine;I-175N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-chloromethyleneoxyphenyl]-2,4-pyrimidinediamine;I-176N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-methylmethyleneoxyphenyl]-2,4-pyrimidinediamine;I-177N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-fluoromethyleneoxyphenyl]-2,4-pyrimidinediamine;I-178N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-pyridylmethoxy)phenyl]-2,4-pyrimidinediamine;I-179N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-1805-Methyl-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-181N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-182N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-183N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-1845-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-185N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-186N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-187N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-188N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-189N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-1905-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-191N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-192N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridinyl)-methylenethiophenyl]-2,4-pyrimidinediamine;I-193N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-194N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-1955-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(4-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-196N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-4-[(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamineHydrochloride Salt; I-197N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-methyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-198N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(1,3-dimethyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine;I-199N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(1-benzyl-3-methyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine;I-200N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(76); I-201N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-202N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-203N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholinoethyloxy)phenyl]-2,4-pyrimidinediamine;I-204N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholinoethyloxy)phenyl]2,4-pyrimidinediamine;I-205N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-morpholinoethyloxy)phenyl)-2,4-pyrimidinediamine;I-206N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-morpholinoethyloxy)phenyl-2,4-pyrimidinediamine;I-2075-Fluoro-N2-(3-morpholinosulfonylphenyl)-N4-[4-(2-morpholinoethyloxy)phenyl]-2,4-pyrimidinediamine;I-208N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholinocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;I-209N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholinocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;I-210N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]-2,4-pyrimidinediamine;I-211N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]-2,4-pyrimidinediamine;I-212N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]-2,4-pyrimidinediamine;I-2135-Fluoro-N4-(4-methoxycarbonylmethoxyphenyl)-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine;I-214N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-2155-Fluoro-N2-[3-(N-methoxycarbonylmethylene)aminosulfonylphenyl]-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-216N2-(3-Aminosulfonyl-5-chloro-4-methylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-217N2-(3-Aminosulfonyl-4-fluoro-5-methylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-218N2-(3-Aminosulfonyl-4-chloro-5-methylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-219N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-220N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-221N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-chloro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine;I-222N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-223N2-(3-Aminosulfonyl-5-chloro-4-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-224N2-(3-Aminosulfonyl-4-fluoro-5-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-225N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-methyl-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-226N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N4-methyl-2,4-pyrimidinediamine; I-227N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-methoxycarbonylmethyl-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-2285-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine;I-2295-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(4-methyl-3-(2-methylpropionyl)aminosulfonylphenyl)-2,4-pyrimidinediamine; I-230N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(59, X = H); I-231N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-232N2-(3-Acetamidosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-233N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-234N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-2355-Fluoro-N2-[3-(N-methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-2365-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediamine;I-237N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[3methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-238N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-2395-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-240N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-241N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-2425-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediaminesodium salt; I-243N2-(3-Acetamidosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediaminesodium salt; I-244N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-245N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-246N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-247N2-{3-[(N-5-Methyl-1,3-dioxolene-2-one-4-yl)methylene]aminosulfonylphenyl}-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-248N2-{3-[N—N-Di-[(5-Methyl-1,3-dioxolene-2-one-4-yl)methylene]]aminosulfonylphenyl}-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-249N2-{3-[N—N-Di-[(5-t-Butyl-1,3-dioxolene-2-one-4-yl)methylene]]aminosulfonylphenyl}-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-250N2-{3-[(N-5-t-Butyl-1,3-dioxolene-2-one-4-yl)methylene]aminosulfonylphenyl}-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-251N2-[3-Aminosulfonyl-4-(4-methylpiperazin-1-yl)phenyl]-5-fluoro-N4-[2-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-252N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(60); I-253N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-254N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-2555-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-256N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-257N2-{3-[(N-5-Methyl-1,3-dioxolene-2-one-4-yl)methylene]aminosulfonylphenyl}-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-258N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-259N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-2605-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-261N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-2625-Fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-N2-[(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediamine;I-263N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-2645-Fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-N2-[(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediamine;I-265N2-(3-Aminosulfonyl-4-chloro-5-methylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine; I-266N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-267N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)ethylenephenyl]-2,4-pyrimidinediamine;I-268N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-[3-methyl-1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4-pyrimidinediamine;I-2695-fluoro-N2-(4-N-methylaminosulfonyl)-3-methoxyphenyl-N4-(4-trifluoromethoxy-3-chlorophenyl)-2,4-pyrimidinediamine;I-2705-fluoro-N4-(3-hydroxyphenyl)-N2-(4-N-methylaminosulfonyl)-3-methoxyphenyl]-2,4-pyrimidinediamine;I-271N2-(5-N,N-Diethylaminosulfonyl-2-methoxyphenyl)-5-fluoro-N4-(4-[3-methyl-1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4-pyrimidinediamine; I-2725-Fluoro-N4-(4-[3-methyl-1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-N2-(5-piperidinesulfonylphenyl)-2,4-pyrimidinediamine;I-2735-Fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-N2-[(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediamineSodium Salt; I-2745-Fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine;I-275N2-(4-Aminosulfonyl)phenyl-5-fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-2,4-pyrimidinediamine;I-276N2-(3-Aminosulfonyl)phenyl-5-fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-2,4-pyrimidinediamine;I-277N2-(3-aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(71); I-278N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-279N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)methoxyphenyl]-2,4-pyrimidinediamine;I-280N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-281N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-2825-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(2-methylthiazol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-283N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methylthizol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-284N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methylthizol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;I-285N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine;II-1 RacemicN2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{3-[(1-methylpiperidin-3-yl)oxy]phenyl}-2,4-pyrimidinediamine;II-2N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{3-[(1-methylpiperidin-4-yl)oxy]phenyl}-2,4-pyrimidinediamine;II-3 RacemicN2-(3-aminosulfonyl-4-methylphenyl)-N4-{3-chloro-4-[(1-methylpiperidin-3-yl)oxy]phenyl}-5-fluoro-2,4-pyrimidinediamine;II-4 RacemicN2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(1-methylpiperidin-3-yl)oxy]phenyl}-2,4-pyrimidinediamine;II-5N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2,4-pyrimidinediamine;II-6N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(1-methylpiperidin-4-yl)oxy]-3-trifluoromethylphenyl}-2,4-pyrimidinediamine;II-7N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2,4-pyrimidinediamine;II-8N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{3-chloro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2,4-pyrimidinediamine;II-9N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(N-methylpyrrolidin-3-yloxyphenyl)-2,4-pyrimidinediamine;II-10N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(N-methylpyrrolidin-3-yloxyphenyl)-2,4-pyrimidinediamine;II-11N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine;II-12N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine;II-135-Fluoro-N2-[3-N-(methylaminosulfonyl)-4-methylphenyl]-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine;II-14N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine;II-15N2-[3,5-bis(Aminosulfonyl)phenyl)-5-fluoro-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine;II-16N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-pyridyloxy)phenyl]-2,4-pyrimidinediamine;II-17N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridyloxy)phenyl]-2,4-pyrimidinediamine;II-185-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(4-pyridyloxy)phenyl]-2,4-pyrimidinediamine;II-19N2-(3-Aminocarbonyl-5-methylphenyl)-5-fluoro-N2-[4-(1-methylpyrazol-3-yl)amidophenyl)-2,4-pyrimidinediamine;II-20N2-(3-Aminocarbonyl-5-methylphenyl)-5-fluoro-N2-[4-(1-ethylpyrazol-5-yl)amidophenyl)-2,4-pyrimidinediamine;II-21N2-(3-Aminocarbonyl-5-methylphenyl)-5-fluoro-N2-[4-(1-methylpyrazol-5-yl)amidophenyl)-2,4-pyrimidinediamine;II-22N2-(3-Aminocarbonyl-5-methylphenyl)-5-fluoro-N2-[4-(1H-pyrazol-5-yl)amidophenyl)-2,4-pyrimidinediamine;III-15-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-(4-cyanomethylphenyl)-2,4-pyrimidinediamine;III-2N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-(4-cyanomethylphenyl)-2,4-pyrimidinediamine;III-3N2-(4-Aminosulfonyl)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-4N2-(3-Aminosulfonyl)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-5N4-(4-Cyanomethyl)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine;III-6N4-(4-Cyanomethyl)phenyl-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine;III-7N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-8N2-(3-Aminosulfonyl-4-chloro)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-9N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-10N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-11N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanoethylenephenyl)-5-methyl-2,4-pyrimidinediamine;III-12N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-[4-(2-cyanoethyl)phenyl]-5-methyl-2,4-pyrimidinediamine;III-13N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-[4-(2-cyanoethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;III-14N2-(3-aminosulfonylphenyl)-N4-[4-(cyanoethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine;III-15N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(cyanoethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine;III-16N2-(3-Aminosulfonyl-4-fluorophenyl)-N4-[4-(cyanoethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine;III-17N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-cyanoethyl)-3-fluorophenyl]-2,4-pyrimidinediamine;III-18N2-(3-Aminosulfonylphenyl)-N4-[4-(2-cyanoethyl)-3-fluorophenyl]-5-fluoro-2,4-pyrimidinediamine;III-19N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(2-cyanoethyl)-3-methylphenyl]-5-fluoro-2,4-pyrimidinediamine;III-20N2-(3-Aminosulfonylphenyl)-N4-[4-(2-cyanoethyl)-3-methylphenyl]-5-fluoro-2,4-pyrimidinediamine;III-21N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-chloro-4-(2-cyanoethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;III-22N2-(3-Aminosulfonylphenyl)-N4-[3-chloro-4-(2-cyanoethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;III-23N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanoethylene-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamineIII-24N2-(3-Aminosulfonylphenyl)-N4-(4-cyanoethylene-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamineIII-25N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanoethylene-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamineIII-26N2-(3-Aminosulfonylphenyl)-N4-(4-cyanoethylene-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamineIII-27N2-(4-Aminosulfonylphenyl)-N4-(4-cyanoethylenephenyl)-5-methyl-2,4-pyrimidinediamineand its prodrug III-28N4-(3-Chloro-4-cyanoethylene-phenyl)-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamineIII-29N4-(3-Chloro-4-cyanoethylene-phenyl)-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamineSodium salt III-30N4-(4-Cyanoethylene-3-trifluoromethylphenyl)-5-fluoro-N2-(4-methyl-3-aminosulfonylphenyl)-2,4-pyrimidinediamineIII-31N4-(4-Cyanoethylene-3-trifluoromethylphenyl)-5-fluoro-N2-(3-aminosulfonylphenyl)-2,4-pyrimidinediamineIII-32N4-(4-Aminocarbonylaminomethylphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-33N4-(4-Aminocarbonylaminomethylphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-34N4-(4-Aminocarbonylaminomethylphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-35N2-(4-aminosulfonyl)phenyl-N4-(4-ethylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-36N2-(3-aminosulfonyl)phenyl-N4-(4-ethylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-37N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(4-ethylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-38N2-(4-aminosulfonyl)phenyl-N4-(3-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-39N2-(3-aminosulfonyl)phenyl-N4-(3-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-40N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(3-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-41N2-(4-aminosulfonyl)phenyl-N4-(4-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-42N2-(3-aminosulfonyl)phenyl-N4-(4-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-43N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(4-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-44N4-(4-Acrylamidomethylphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-45N4-(4-Acrylamidomethylphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-46N4-(4-Acrylamidomethylphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-47N4-[4-(2-Aminocarboxylethylene)phenyl]-5-fluoro-N2-(4-methyl-3-aminosulfonylphenyl)-2,4-pyrimidinediamine;III-48N4-[4-(2-Aminocarboxylethylene)phenyl]-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamineIII-49N4-[4-(2-Aminocarboxylethylene)phenyl]-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamineIII-50N2-(3-Aminosulfonylphenyl)-5-fluoro-N-4-[4(1-methylpyrazolyl-3-aminocarbonylmethylene)phenyl]-2,4-pyrimidinediamine;III-51N2-(3-Aminosulfonylphenyl)-N4-[(1-ethylpyrazolyl-5-aminocarbonylmethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine;III-52N2-(3-Aminosulfonyl-4-methylphenyl)-5-N4-[(1-ethylpyrazolyl-5-aminocarbonylmethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine;III-53N4-{4-[2-(Aminocarbonyloxy)ethyl]phenyl}-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-54N4-{4-[2-(Aminocarbonyloxy)ethyl]phenyl}-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-55N4-{4-[2-(Aminocarbonyloxy)ethyl]phenyl}-N2-(3-aminosulfonyl-4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine;III-56N2-(3-Aminosulfonyl-4-methylphenyl)-N4-{4-[2-(dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-2,4-pyrimidinediamine;III-57N2-(3-Aminosulfonylphenyl)-N4-{4-[2-(dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-2,4-pyrimidinediamine;III-58N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-{4-[2-(dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-2,4-pyrimidinediamine;III-59N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[2-(methylaminocarbonyloxy)ethyl]phenyl}-2,4-pyrimidinediamine;III-60N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[2-(methylaminocarbonyloxy)ethyl]phenyl}-2,4-pyrimidinediamine;III-61N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-{4-[2-(methylaminocarbonyloxy)ethyl]phenyl}-2,4-pyrimidinediamine;III-62N2-(3-Aminosulfonylphenyl)-N4-(4-benzylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-63N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-benzylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-64N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(4-benzylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-65N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(4-benzylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-66N2-(3-Aminosulfonyl-4-methoxyphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;III-67N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;III-685-Fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-N2-[(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediamine;III-695-Fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-N2-[(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediaminesodium salt; III-70N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;III-71N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;III-72N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;III-73N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridylmethyl)phenyl]-2,4-pyrimidinediamineHydrochloride Salt; III-74N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;III-755-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;III-76N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)phenethyl]-2,4-pyrimidinediamine;III-77N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)phenethyl]-2,4-pyrimidinediamine;III-785-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(4-pyridinyl)phenethyl]-2,4-pyrimidinediamine;III-79N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)phenethyl]-2,4-pyrimidinediamine;III-80 Preparation ofN2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-oxido-4-pyridylmethyl)phenyl]-2,4-pyrimidinediamine;III-81N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine;III-82N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine;III-835-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine;III-84N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine;III-855-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediaminehydrochloride III-865-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediaminedihydrochloride III-87N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-imidazolyl)phenethyl]-2,4-pyrimidinediamine;III-88N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1-imidazolyl)phenethyl]-2,4-pyrimidinediamine;III-895-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1-imidazolyl)phenethyl]-2,4-pyrimidinediamine;III-90N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-imidazolyl)phenethyl]-2,4-pyrimidinediamine;III-91N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-methyl-1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine;III-92N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methyl-1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine;III-935-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(2-methyl-1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine;III-94N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methyl-1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine;III-95N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine;III-96N2-4-Aminosulfonylphenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine;III-97N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine;III-985-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-{4-[1-(1,2,3-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine;III-99N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-{4-[1-(1,2,4-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine;III-100N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[1-(1,2,4-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine;III-101N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[1-(1,2,4-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine;III-1025-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-{4-[1-(1,2,4-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine;III-103N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-N-morpholinomethylenephenyl)-2,4-pyrimidinediamine;III-104N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-N-morpholinomethylenephenyl)-2,4-pyrimidinediamine;III-105N2-(3-Aminosulfonyl-4-methyleneoxyphenyl)-5-fluoro-N4-(4-N-morpholinomethylenephenyl)-2,4-pyrimidinediamine;III-106N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)ethylenephenyl]-2,4-pyrimidinediamine;III-107N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-thiomorpholinomethylenephenyl)-2,4-pyrimidinediamine;III-108N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-thiomorpholinomethylenephenyl)-2,4-pyrimidinediamine;III-109N2-(3-Aminosulfonyl-4-methyoxyphenyl)-5-fluoro-N4-(4-thiomorpholinomethylenephenyl)-2,4-pyrimidinediamine;III-110N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[(1,1-dioxothiomorpholin-4-yl-)methyl]phenyl}-2,4-pyrimidinediamine;III-111N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(1,1-dioxothiomorpholin-4-yl-)methyl]phenyl}-2,4-pyrimidinediamine;III-112N2-(3-Aminosulfonyl-4-methyloxyphenyl)-5-fluoro-N4-{4-[(1,1-dioxothiomorpholin-4-yl-)methyl]phenyl}-2,4-pyrimidinediamine;III-113N4-(3-aminocarbonylaminomethyl)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-114N4-(3-aminocarbonylaminomethyl)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-115N4-(3-aminocarbonylaminomethyl)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-116N2-(4-aminosulfonyl)phenyl-N4-(3-ethylaminocarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-117N2-(3-aminosulfonyl)phenyl-N4-(3-ethylaminocarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-118N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(3-ethylaminocarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;III-119N2-(4-Aminosulfonylphenyl)-N4-(4-ethylaminocarbonylaminomethylphenyl]-5-fluoro-2,4-pyrimidinediamine;III-120N2-(3-Aminosulfonylphenyl]-N4-(4-ethylaminocarbonylaminomethylphenyl)-5-fluoro-2,4-pyrimidinediamine;III-121N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-ethylaminocarbonylaminomethylphenyl)-5-fluoro-2,4-pyrimidinedia;III-122N2-(4-aminosulfonyl)phenyl-N4-[4-(2-ethylaminocarbonylamino)ethyl]phenyl-5-fluoro-2,4-pyrimidinediamine;III-123N2-(3-aminosulfonyl)phenyl-N4-[4-(2-ethylaminocarbonylamino)ethyl]phenyl-5-fluoro-2,4-pyrimidinediamine;III-124N2-(3-aminosulfonyl-4-methyl)phenyl-N4-[4-(2-ethylaminocarbonylamino)ethyl]phenyl-5-fluoro-2,4-pyrimidinediamine;III-125N2-(4-aminosulfonyl)phenyl-N4-[4-(N-carbamoyl-N-propyl)aminomethyl]phenyl-5-fluoro-2,4-pyrimidinediamine;III-126N2-(3-aminosulfonyl)phenyl-N4-[4-(N-carbamoyl-N-propyl)aminomethyl]phenyl-5-fluoro-2,4-pyrimidinediamine;III-127N2-(3-aminosulfonyl-4-methyl)phenyl-N4-[4-(N-carbamoyl-N-propyl)aminomethyl]phenyl-5-fluoro-2,4-pyrimidinediamine;III-128N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridylmethyl)phenyl]-2,4-pyrimidinediaminep-Toluenesulfonic Acid Salt; III-129N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridylmethyl)phenyl]-2,4-pyrimidinediamineMethanesulfonic Acid Salt; IV-1N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine;IV-2N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine;IV-3N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine;IV-45-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine;IV-5N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine;IV-6N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine;IV-75-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine;IV-8N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine;IV-9N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(N,N-dimethylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;IV-10N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(N,N-dimethylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;IV-11N2-(3-Aminosulfonylhenyl)-5-fluoro-N4-[3-(N-methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;IV-12N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(N-methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;V-1N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[2-(5-methylisoxazol-3-yl)methyleneoxypyridin-5-yl]-2,4-pyrimidinediamine;V-2N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethy)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;V-3N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethy)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;V-4 RacemicN2-(4-Aminosulphonylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;V-5 RacemicN2-(3-Aminosulphonylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;V-6N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;V-7N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;V-8N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[3-oxo-4-cyanomethyl-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;V-9(R/S)—N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benzo[1,4]thiazin-6-yl]-2,4-pyrimidinediamine; V-10(R/S)—N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benzo[1,4]thiazin-6-yl]-2,4-pyrimidinediamine;V-11N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;V-12N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;V-13N2-(3-Aminosulphonyl4-methylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;V-14N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[2,2-dimethyl-3-oxo-4-cyanomethyl-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;V-15N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-[2,2-dimethyl-3-oxo-4-cyanomethyl-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;V-16N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(2-cyanoethylene-benzothiophen-5-yl)-5-fluoro-2,4-pyrimidinediamineV-17N-2-(3-aminosulfonylphenyl)-N4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;V-18N-2-(3-aminosulfonyl-4-methylphenyl)-N4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;V-19(4R)—N2-(3-aminosulfonyl-4-methylphenyl)-N4-(1-cyanomethylenecarbonyl-4-methylpiperidin-3-yl)-5-fluoro-2,4-pyrimidinediamine)or(4S)—N2-(3-aminosulfonyl-4-methylphenyl)-N4-(1-cyanomethylenecarbonyl-4-methylpiperidin-3-yl)-5-fluoro-2,4-pyrimidinediamine)VIII-15-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(sacchrin-6-yl)-2,4-pyrimidinediamine;and VIII-2N4-(3-Chloro-4-cyanomethyleneoxyphenyl)-5-fluoro-N2-(5-methyl-2H-1,1-dioxide-1,2,4-benzothiadiazin-7-yl)-2,4-pyrimidinediamine.

Another embodiment of the invnetion provides compounds selected from thegroup consisting of:

cmpd name VI-15-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(N-methyl)aminosulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine;VI-2N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-3N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine;VI-4N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-5N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-6N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine;VI-7N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methoxycarbonylmethylene)aminosulfonylphenyl]-2,4-pyrimidinediamine;VI-8N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[3-(N-methoxycarbonylmethylene)aminosulfonylphenyl]-2,4-pyrimidinediamine;VI-9N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[3-(4-methylpiperidin-1-yl)aminosulfonylphenyl]-2,4-pyrimidinediamine;VI-10N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[3-(4-methylpiperidin-1-yl)aminosulfonylphenyl]-2,4-pyrimidinediamine;VI-11N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-12N2-[3-(N-Acetyl)aminosulfonyl-4-chlorophenyl]-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-13N2-(3-Aminosulfonyl-5-chloro-4-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-14N2-(3-Aminosulfonyl-5-chloro-4-methylphenyl)-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-15N2-(3-Aminosulfonyl-4-fluoro-5-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-16N2-(3-Aminosulfonyl-4-fluoro-5-methylphenyl)-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-17N2-(3-Aminosulfonyl-4-chloro-5-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-18N2-(3-Aminosulfonyl-4-chloro-5-methylphenyl)-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-19N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-methyl-2,4-pyrimidinediamine;VI-20N2-(3-Aminosulfonyl-4-fluoro-5-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-methyl-2,4-pyrimidinediamine;VI-21N2-(3-Aminosulfonyl-4-chloro-5-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-methyl-2,4-pyrimidinediamine;VI-22N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-propyl-2,4-pyrimidinediamine;VI-23N2-(3-Aminosulfonyl-4-fluoro-5-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-propyl-2,4-pyrimidinediamine;VI-24N2-(3-Aminosulfonylphenyl)-5-carboethoxy-N4-(N-carboethoxymethylene-N-3-chloro-4-methoxyphenyl)-2,4-pyrimidinediamine;VI-25N2-(3-Aminosulfonyl-4-methylphenyl)-5-carboethoxy-N4-(N-carboethoxymethylene-N-3-chloro-4-methoxyphenyl)-2,4-pyrimidinediamine;VI-26N2-(3-aminosulfonylphenyl)-5-bromo-N4-(3-chloro-4-methoxyphenyl)-2,4-pyrimidinediamine;VI-272-(3-aminosulfonyl-4-methylphenyl)-5-bromo-N4-(3-chloro-4-methoxyphenyl)-2,4-pyrimidinediamine;VI-28N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-trimethylsilylacetylene-2,4-pyrimidinediamine;VI-29N2-(3-Aminosulfonyl-4-methoxyphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-30N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-31N2-(3-Aminosulfonylpyrid-4-yl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-32N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-trofluoromethoxyphenyl)-2,4-pyrimidinediamine;VI-33N2-(3-aminosulfonylphenyl)-5-fluoro-N4-(4-trofluoromethoxyphenyl)-2,4-pyrimidinediamine;VI-34N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-5-fluoro-N4-(4-trifluoromethylphenyl)-2,4-pyrimidinediamine;VI-35N2-(3-Aminosulfonylphenyl)-N4-(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-36N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-37N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-38N2-(3-Aminosulfonylphenyl)-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-39N2-(3-Aminosulfonyl-4-methyl-phenyl)-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-40N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(4-chloro-3-trifluoromethyl-phenyl)-5-fluoro-2,4-pyrimidinediamine;VI-41N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-(4-trifluorophenyl)-2,4-pyrimidinediamine;VI-42N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-(4-trifluoromethoxyphenyl)-2,4-pyrimidinediamine;VI-43N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-44N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-trifluoromethyl-phenyl)-5-fluoro-2,4-pyrimidinediamine;VI-45N2-(3-Aminosulfonyl-4-iso-propylphenyl)-N4-(3-chloro-4-methoxy-phenyl)-5-fluoro-2,4-pyrimidinediamine;VI-46N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-trifluoromethylmethyleneoxyphenyl)-2,4-pyrimidinediamine;VI-47N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-trifluoromethylmethyleneoxyphenyl)-2,4-pyrimidinediamine;VI-48N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-(4-trifluoromethylmethyleneoxyphenyl)-2,4-pyrimidinediamine;VI-49N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(methylaminocarbonyloxymethyl)phenyl]-2,4-pyrimidinediamine;VI-50N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-trifluoromethylphenyl)-2,4-pyrimidinediamine;VI-51N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-trifluoromethylphenyl)-2,4-pyrimidinediamine;VI-52N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-hydroxymethylphenyl)-2,4-pyrimidinediamine;VI-53N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-54N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-vinylphenyl)-2,4-pyrimidinediamine;VI-55N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-565-Fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-57N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-58N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-methyl-4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-59N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-chloro-4-(prop-2-ynyloxy)phenyl]-5-fluoro-2,4-pyrimidinediamine;VI-60N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-61N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(but-2-ynyloxy)phenyl]-5-fluoro-2,4-pyrimidinediamine;VI-62N2-[3-propionylaminosulfonyl-4-methylphenyl]-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-63N2-[3-Aminosulfonyl-4-(2-propyl)phenyl]-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-64N4-{4-[2-(Dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-N2-(3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine;VI-65N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynylamino)phenyl]-2,4-pyrimidinediamine;VI-66N4-{4-[2-(Dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-N2-(3-propionylaminosulfonylphenyl)-2,4-pyrimidinediaminesodium salt VI-67N2-(3-Aminosulfonyl-4-methylphenyl)-N4-{4-[bis(prop-2-ynyl)amino]phenyl}-5-fluoro-2,4-pyrimidinediamine;VI-685-Fluoro-N2-(4-methyl-3-methylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-695-Fluoro-N2-{[4-methyl-3-((1-methylpiperidin-4-yl)aminosulfonyl)]phenyl}-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-70N2-[3-Aminosulfonyl-4-(1-methylpiperazin-4-yl)phenyl]-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-71N4-{4-[2-(Aminocarbonylamino)ethyl]phenyl}-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-72N4-{4-[2-(Aminocarbonylamino)ethyl]phenyl}-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-73N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(prop-2-ynyloxy)carbonylaminomethyl]phenyl}-2,4-pyrimidinediamine;VI-74N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[(prop-2-ynyloxy)carbonylaminomethyl]phenyl}-2,4-pyrimidinediamine;VI-75N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;VI-76N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;VI-77N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine; VI-785-Fluoro-N2-[3-(prop-2-ynylaminosulfonyl)phenyl]-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;VI-79N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;VI-80N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;VI-81N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;VI-82N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-pyrimidinediamine;VI-83N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-pyrimidinediamine;VI-84N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-pyrimidinediamine;VI-85N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-hydroxypropyl)phenyl]-2,4-pyrimidinediamine;VI-86N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-hydroxypropyl)phenyl]-2,4-pyrimidinediamine;VI-87N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-hydroxypropyl)phenyl]-2,4-pyrimidinediamine;VI-88N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-hydroxybutyl)phenyl]-2,4-pyrimidinediamine;VI-89N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-hydroxybutyl)phenyl]-2,4-pyrimidinediamine;VI-90N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-hydroxybutyl)phenyl]-2,4-pyrimidinediamine;VI-91N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-fluorobutyl)phenyl]-2,4-pyrimidinediamine;VI-92N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-fluorobutyl)phenyl]-2,4-pyrimidinediamine;VI-93N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-fluorobutyl)phenyl]-2,4-pyrimidinediamine;VI-94N2-(4-aminosulfonyl)phenyl-5-fluoro-N4-(4-thiomethylcarbonyl)phenyl-2,4-pyrimidinediamine;VI-95N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-N4-(4-thiomethylcarbonyl)phenyl-2,4-pyrimidinediamine;VI-96N2-(3-Butylaminosulfonylphenyl)-N4-(3-cyano-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-97N2-(3-Butylaminosulfonylphenyl)-N4-(3-chloro-4-fluorophenyl)5-fluoro-2,4-pyrimidinediamine;VI-98N2-(3-Aminosulfonylphenyl)-N4-(3-cyano-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine;VI-99N2-(3-Aminosulfonylphenyl)-N4-(3-cyano-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-100N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(4-hydroxyphenyl)-2,4-pyrimidinediamine;VI-101N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-hydroxyphenyl)-2,4-pyrimidinediamine;VI-102N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-hydroxyphenyl]-2,4-pyrimidinediamine;VI-103N4-[4(2-Cyanoethyl)-3-methylphenyl]-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine;VI-104N4-[4-(2-Cyanoethyl)-3-methylphenyl]-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamineSodium Salt; VI-105N4-(3,4-dichlorophenyl)-N4-methyl-5-fluoro-N2-[3-(N,N-diethyl)aminosulfonyl-4-methoxyphenyl]-2,4-pyrimidinediamine;VI-106N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-methoxy-3-chlorophenyl]-2,4-pyrimidinediamine;VI-107N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-methoxy-3-chlorophenyl]-2,4-pyrimidinediamine;VI-108N4-(3-chloro-4-methoxyphenyl)-N2-(3-N,N-diethylaminosulfonyl-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-109N2-(4-Aminosulfonylphenyl)-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine;VI-110N2-(3-Aminosulfonylphenyl)-N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine;VI-111N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-[4-(2-methoxyethyleneoxy)phenyl]-2,4-pyrimdinediamine;VI-112N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-methoxyethyleneoxy)phenyl]-2,4-pyrimdinediamine;VI-113 N2,N4-Bis-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-114N2,N4-Bis-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;VI-115N2,N4-Bis-(3-aminosulfonyl-4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine;VI-116N2-[3-Aminosulfonyl-4-(4-methylpiperazine-1-yl)phenyl]-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;VII-1N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[(2S,4R)-1-(2-cyanoacetyl)-2-methoxycarbonylpyrrolidin-4-yl)-5-fluoro-2,4-pyrimidinediamine;VII-2N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[(2S,4S)-1-(2-cyanoacetyl)-2-methoxycarbonylpyrrolidin-4-yl]-5-fluoro-2,4-pyrimidinediamine;VII-3 RacemicN2-(3-aminosulfonyl-4-methylphenyl)-N4-(1-benzyl-4-methylpiperidin-3-yl)-5-fluoro-2,4-pyrimidinediamine;VII-4 RacemicN2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-methylpiperidin-3-yl)-2,4-pyrimidinediamine;VII-5 RacemicN2-(3-aminosulfonyl-4-methylphenyl)-N4-(1-cyanomethylenecarbonyl-4-methylpiperidin-3-yl)-5-fluoro-2,4-pyrimidinediamine;VII-6N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(2-methoxypyrid-5-yl)-2,4-pyrimidinediamine;VII-7N2-(3-Aminosulfonylphenyl)-N4-(2-amino-3-methoxypyrid-6-yl)-5-fluoro-2,4-pyrimidinediamine;VII-8N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(2-amino-3-methoxypyrid-6-yl)-5-fluoro-2,4-pyrimidinediamine;VII-9N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[2-amino-3-methoxypyrid-6-yl]-5-fluoro-2,4-pyrimidinediamine(66); VII-10N4-(2-Amino-3-methoxypyrid-6-yl)-N2-[3-(ethoxycarbonylmethylene)aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;VII-11N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(2,2,4-trimethyl-1,1,3-trioxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-12N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(2,2,4-trimethyl-1,1,3-trioxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-13N2-(4-aminosulfonyl)phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-5-fluoro-2,4-pyrimidinediamineVII-14N2-(3-aminosulfonyl)phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-5-fluoro-2,4-pyrimidinediamineVII-15N2-(3-aminosulfonyl-4-methyl)phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-5-fluoro-2,4-pyrimidinediamineVII-16N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(1,2,3,4-tetrahydroisoquin-7-yl)-2,4-pyrimidinediamine;VII-17N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[2-(methylaminocarbonyl)-1,2,3,4-tetrahydroisoquin-7-yl]-2,4-pyrimidinediamine;VII-18N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[2-(dimethylaminocarbonyl)-1,2,3,4-tetrahydroisoquin-7-yl]-2,4-pyrimidinediamine;VII-19N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[1-(methylaminocarbonyl)-1,2,3,4-tetrahydroquin-6-yl]-2,4-pyrimidinediamine;VII-20N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(methylaminocarbonyl)-1,2,3,4-tetrahydroquin-6-yl]-2,4-pyrimidinediamine;VII-21N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3,4-dihydro-(1H)-quinolin-2-one-6-yl]-5-fluoro-2,4-pyrimidinediamineVII-22N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(3-methoxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine;VII-23N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(2-methoxyethyl)indazolin-5-yl]-2,4-pyrimidinediamine;VII-24N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-2,4-pyrimidinediamine;VII-25N4-(3,4-Ethyenedioxyphenyl)-5-fluoro-N2-[4-(N-methyl)aminosulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine;VII-26 RacemicN2-(3-Aminosulfonyl-4-methylphenyl)-N4-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine; VII-27 RacemicN2-(3-Aminosulfonyl-4-chlorophenyl)-N4-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine; VII-28N2-(3-Aminosulfonylphenyl)-N4-(chroman-4-amine-6-yl)-5-fluoro-2,4-pyrimidinediamine;VII-29N2-(4-Aminosulfonylphenyl)-N4-(chroman-4-amine-6-yl)-5-fluoro-2,4-pyrimidinediamine;VII-30N2-(3-Aminosulphonyl-4-methylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;VII-31N2-(4-Aminosulphonylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;VII-32N2-(3-Aminosulphonylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;VII-33N2-(3-Aminosulphonyl-4-methylphenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-34N2-(4-Aminosulphonylphenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-35N2-(3-Aminosulphonylphenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-36N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-37N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[4-(N-methyl)aminosulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine;VII-38N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(2,2-difluoro-4H-benz[1,4]oxazin-3-on-6-yl)-5-fluoro-2,4-pyrimidinediamine;VII-395-Amino-N2-(3-amionsulfonylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;VII-40N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;VII-41N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;VII-42N2-(3-Aminosulfonylphenyl)-N4-[2,2,4-trimethyl-3-oxo-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;VII-43N2-(4-Aminosulfonylphenyl)-N4-[2,2,4-trimethyl-3-oxo-5-pyrid[1,4]oxazin-5-yl]-5-fluoro-2,4-pyrimidinediamine;VII-44N2-(3-Aminosulphonyl-4-methyl-phenyl)-5-fluoro-N4-(3-oxo-4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-45N2-(3-Aminosulphonyl-4-methyl-phenyl)-5-fluoro-N4-(3-oxo-4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-46N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(2,2,4-trimethyl-1,1,3-trioxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-47N2-(4-Aminosulphonylphenyl)-N4-cyanomethyl-5-fluoro-N4-[3-oxo-4-methyl-benzo[1,4]thiazin-6-yl]-2,4-pyrimidinediamine;VII-48N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-49N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;VII-505-Fluoro-N4-(4-methyl-3-oxo-benz[1,4]thiazin-6-yl)-N2-(3-piperidinosulfonylphenyl)-2,4-pyrimidinediamine;VII-51N2-(3-Aminosulfonylphenyl)-N4-[2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;VII-52N2-(4-Aminosulfonylphenyl)-N4-[2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;VII-53N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(2-cyanobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine;VII-54N2-(3-Aminosulfonylphenyl)-N4-(2-aminocarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine;VII-55N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-[4-(3-pyridinylmethyl)benzo[1,4]oxazin-7-yl]-2,4-pyrimidinediamine;VII-56N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-[4-(3-pyridinylmethyl)benzo[1,4]oxazin-7-yl]-2,4-pyrimidinediamine;VII-57N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(benzothiophen-5-yl)-5-fluoro-2,4-pyrimidinediamine;VII-58N2-(3-Aminosulfonylphenyl)-N4-(benzothiophen-5-yl)-5-fluoro-2,4-pyrimidinediamine;VII-59N2-(4-Aminosulfonylphenyl)-N4-(4-N-tert-butoxycarbonylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-2,4-pyrimidinediamine;VII-60N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-methylsulfonyl)indolin-5-yl]-2,4-pyrimidinediamine;VII-61N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1-methylsulfonyl)indolin-5-yl]-2,4-pyrimidinediamine;VII-625-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1-methylsulfonyl)indolin-5-yl]-2,4-pyrimidinediamine;VII-63N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-methylsulfonyl)indolin-5-yl]-2,4-pyrimidinediamine;VII-64N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-2-yl)-2,4-pyrimidinediamine;VII-65N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-3-yl)-2,4-pyrimidinediamine;VII-66N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(quinolin-3-yl)-2,4-pyrimidinediamine;VII-67N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-5-yl)-2,4-pyrimidinediamine;VII-68N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(quinolin-5-yl)-2,4-pyrimidinediamine;VII-69N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-6-yl)-2,4-pyrimidinediamine;VII-70N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(quinolin-6-yl)-2,4-pyrimidinediamine;VII-71N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(2-methylquinolin-6-yl)-2,4-pyrimidinediamine;VII-72N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(2-methylquinolin-6-yl)-2,4-pyrimidinediamine;VII-73N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(2-hydroxy-4-methylquinolin-6-yl)-2,4-pyrimidinediamineVII-74N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(2-hydroxy-4-methylquinolin-6-yl)-2,4-pyrimidinediamineVII-75N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(2-N,N′-dimethylamine-quinolin-6-yl)-5-fluoro-2,4-pyrimidinediamineVII-76N2-(3-Aminosulfonylphenyl)-N4-(2-N,N′-dimethylamine-quinolin-6-yl)-5-fluoro-2,4-pyrimidinediamineVII-77N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-8-yl)-2,4-pyrimidinediamine;VII-78N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(quinolin-8-yl)-2,4-pyrimidinediamine;VII-79N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(quinolin-8-yl)-2,4-pyrimidinediamine;VII-80N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(2-methylquinolin-8-yl)-2,4-pyrimidinediamine;VII-81N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(2-methylquinolin-8-yl)-2,4-pyrimidinediamine;VII-82 (1R,2R,3S,4S)N4-(3-Aminocarbonylbicyclo[2.2.1]hept-5-en-2-yl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;VII-83 (1R,2R,3S,4S)N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-ene-2-yl)-5-fluoro-2,4-pyrimidinediamine; and VIII-3N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(5-methyl-2H-1,1-dioxo-1,2,4-benzothiadiazin-7-yl)-2,4-pyrimidinediamine.

Yet another aspect of the invention provides compounds selected from thegroup consisting of:

cmpd name IX-1N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-5-yl]-2,4-pyrimidinediamine;IX-2N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-5-yl]-2,4-pyrimidinediamine;IX-3N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-6-yl]-2,4-pyrimidinediamine;IX-4N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-6-yl]-2,4-pyrimidinediamine;IX-5N2-(3-Aminosulfonylphenyl)-N4-(1-cyanomethyleneindol-5-yl)-5-fluoro-2,4-pyrimidinediamine;IX-6N2-(4-Aminosulfonylphenyl)-N4-(1-cyanomethyleneindol-5-yl)-5-fluoro-2,4-pyrimidinediamine;IX-7N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(1-cyanomethyleneindol-5-yl)-5-fluoro-2,4-pyrimidinediamine;IX-8N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(1-cyanomethyleneindol-5-yl)-5-fluoro-2,4-pyrimidinediamine;IX-9N4-[3-(Aminocarbonyl)-1H-indol-6-yl]-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;IX-10N4-[3-(Aminocarbonyl)-1H-indol-6-yl]-N2-(3-aminosulfonyl-4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine;IX-11N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-cyanomethyl-1H-indol-6-yl)-5-fluoro-2,4-pyrimidinediamine;IX-12N2-(3-Aminosulfonylphenyl)-N4-(3-cyanomethyl-1H-indol-6-yl)-5-fluoro-2,4-pyrimidinediamine;IX-13N2-(3-Aminosulfonylphenyl)-N4-(3-cyanomethyl-1H-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine;IX-14N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-cyanomethyl-1H-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine;IX-15N2-(3-Aminosulfonylphenyl)-N4-(3-cyanomethyl-1H-indol-7-yl)-5-fluoro-2,4-pyrimidinediamine;IX-16N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-cyanomethyl-1H-indol-7-yl)-5-fluoro-2,4-pyrimidinediamine;IX-17N2-[3-Aminosulfonyl-4-(4-methylpiperazine-1-yl)phenyl]-N4-(3-cyanomethylene-1H-indol-6-yl)-5-fluoro-2,4-pyrimidinediamine;IX-18N2-[3-Aminosulfonyl-4-(4-methylpiperazine-1-yl)phenyl]-N4-(3-cyanomethylene-1H-indol-7-yl)-5-fluoro-2,4-pyrimidinediamine;IX-19N4-(3-cyanomethylene-1H-indol-5-yl)-5-fluoro-N2-[3-(1-methyl-4-aminopiperadine)sulfonyl-4-methylphenyl]-2,4-pyrimidinediamine; IX-20N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-cyanomethyl-1-methyl-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine;IX-21N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(2-cyanobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine;IX-22N2-(3-Aminosulfonyl-4-iso-propylphenyl)-N4-(2-cyanobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine;IX-23N4-[4-(1-Acetyl-4-piperizinyl)carbonylphenyl]-N2-(3-Aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;IX-24N4-[4-(1-Acetyl-4-piperizinyl)carbonylphenyl]-N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;IX-25N4-[4-(1-Acetyl-4-piperizinyl)carbonylphenyl]-5-fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-2,4-pyrimidinediamine;IX-26N4-[4-(1-Acetyl-4-piperizinyl)carbonylphenyl]-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;IX-27N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-methylpiperazin-1-ylcarbonyl)phenyl]-2,4-pyrimidinediamine;IX-28N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-methylpiperazin-1-ylcarbonyl)phenyl]-2,4-pyrimidinediamine;IX-29N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-methanesulfonyl-4-piperizinyl)carbonylphenyl]-2,4-pyrimidinediamine;IX-30N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1-methanesulfonyl-4-piperizinyl)carbonylphenyl]-2,4-pyrimidinediamine;IX-315-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(1-methanesulfonyl-4-piperizinyl)carbonylphenyl]-2,4-pyrimidinediamine; IX-32N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-methanesulfonyl-4-piperazinyl)carbonylphenyl]-2,4-pyrimidinediamine;IX-335-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(4-thiomorpholino)carbonylphenyl]-2,4-pyrimidinediamine;IX-34N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-thiomorpholinyl)carbonylphenyl]-2,4-pyrimidinediamine;IX-35N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-thiomorpholinyl)carbonylphenyl]-2,4-pyrimidinediamine;IX-36N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-thiomorpholinyl)carbonylphenyl]-2,4-pyrimidinediamine;IX-37N2-(3-Aminosulfonylphenyl)-N4-[4-(1,1-dioxo-4-thiomorpholinyl)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine;IX-38N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(1,1-dioxo-4-thiomorpholinyl)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine;IX-39N4-[4-(1,1-dioxo-4-thiomorpholinyl)carbonylphenyl]-5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-2,4-pyrimidinediamine; IX-40N2-(4-Aminosulfonylphenyl)-N4-[4-(1,1-dioxo-4-thiomorpholinyl)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine;IX-41N4-(4-Acetylthiomethylcarbonylphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;IX-42N4-(4-Acetylthiomethylcarbonylphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;IX-43N4-(4-Acetylthiomethylcarbonylphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;IX-44N2-(4-Aminosulfonylphenyl)-N4-[3,5-dimethyl-4-(4-methylpiperazin-1-yl]phenyl)-5-fluoro-2,4-pyrimidinediamine;IX-45N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[(4R)-1-(2-cyanoacetyl)-pyrrolidin-4-yl)-5-fluoro-2,4-pyrimidinediamineIX-46N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2,4-pyrimidinediamineIX-47N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2,4-pyrimidinediamineIX-48N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2,4-pyrimidinediamineIX-49N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2,4-pyrimidinediamineIX-50N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[4-(N-methyl)aminosulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine;IX-51N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[4-(N-methyl)aminosulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine;IX-52N4-(4-Chloro-3-trifluoromethylphenyl)-5-fluoro-N2-[4-(N-methyl)aminosulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine;IX-53N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[4-(N-methyl)aminosulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine;IX-545-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(2-pyridinyl)-3-chloromethyleneoxyphenyl]-2,4-pyrimidinediamine;X-16-carbonylmethoxy-N4-(3,4-dichlorophenyl)-N2-(3-N,N-diethylaminosulfonyl-6-methoxyphenyl)-2,4-pyrimidinediamine;X-26-carbonylmethoxy-(3-N,N-diethylaminosulfonyl-6-methoxyphenyl)-N4-[3-oxo-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;and X-3N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(2-methylindol-6-ylmethylene)-2,4-pyrimidinediamine.

In another embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting in vitro a JAK3 kinasewith an amount of a compound effective to inhibit an activity of the JAKkinase wherein the compound is selected from the compounds of thisinvention, as described herein, and the compounds of Table XI (CAS Reg.No. 845817-97-2, CAS Reg. No. 841290-42-4, and CAS Reg. No.841290-41-3).

In another embodiment, this invention provides a method of treating aT-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound effective to treat the autoimmune disease wherein the compoundis selected from the compounds of this invention, as described herein,and the compounds of Table XI (CAS Reg. No. 845817-97-2, CAS Reg. No.841290-42-4, and CAS Reg. No. 841290-41-3).

In yet another embodiment, this invention provides a method of treatinga T-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound effective to treat the autoimmune disease wherein the compoundis selected from the compounds of this invention, as described herein,and the compounds of Table XI (CAS Reg. No. 845817-97-2, CAS Reg. No.841290-42-4, and CAS Reg. No. 841290-41-3) and the compound isadministered in combination with, or adjunctively to, a compound thatinhibits Syk kinase with an IC₅₀ in the range of 10 μM or less.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient,comprising administering to the transplant recipient an amount of acompound effective to treat or prevent the rejection wherein thecompound is selected from the compounds of this invention, as describedherein, and the compounds of Table XI (CAS Reg. No. 845817-97-2, CASReg. No. 841290-42-4, and CAS Reg. No. 841290-41-3). The rejection canbe acute rejection or chronic rejection. The rejection can also bemediated by HVGR or GVHR. In certain embod iments, the allografttransplant is selected from a kidney, a hear, a liver and a lung. Thecompound, optionally, can be administered in combination with, oradjunctively to, an immunosuppressant. In certain preferred embodiments,the immunosuppressant is selected from cyclosporine, tacrolimus,sirolimus, an inhibitor of IMPDH, mycophenolate, mycophanolate mofetil,an anti-T-Cell antibody and OKT3.

In another embodiment, this invention provides a method of treating orpreventing a Type IV hypersensitivity reaction, comprising administeringto a subject an amount of a compound of effective to treat or preventthe hypersensitivity reaction wherein the compound is selected from thecompounds of this invention, as described herein, and the compounds ofTable XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3). In a preferred embodiment, the compound isadministered prior to exposure to an allergen.

In another embodiment, this invention provides a method of inhibiting asignal transduction cascade in which JAK3 kinase plays a role,comprising contacting a cell expressing a receptor involved in such asignaling cascade with a compound wherein the compound is selected fromthe compounds of this invention, as described herein, and the compoundsof Table XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease wherein the compound is selected from thecompounds of this invention, as described herein, and the compounds ofTable XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3). In a preferred embodiment, the JAK-mediatedisease is selected from the group consisting of HVGR, GVHR, acuteallograft rejection, and hronic allograft rejection.

In another embodiment, this invention provides a pharmaceuticalformulation comprising a compound selected from the compounds of thisinvention, as described herein, and the compounds of Table XI (CAS Reg.No. 845817-97-2, CAS Reg. No. 841290-42-4, and CAS Reg. No. 841290-41-3)or a prodrug thereof, and at least one pharmaceutically acceptableexcipient, diluent, preservative, or stabilizer, or mixtures thereof.

In another embodiment, this invention provides a kit comprising acompound selected from the compounds of this invention, as describedherein, and the compounds of Table XI (CAS Reg. No. 845817-97-2, CASReg. No. 841290-42-4, and CAS Reg. No. 841290-41-3) or a prodrugthereof, packaging and instructions for use. In a preferred embodiment,the kit includes a pharmaceutical formulation comprising a compoundselected from the compounds of this invention, as described herein, andthe compounds of Table XI (CAS Reg. No. 845817-97-2, CAS Reg. No.841290-42-4, and CAS Reg. No. 841290-41-3) or a prodrug thereof, and atleast one pharmaceutically acceptable excipient, diluent, preservative,or stabilizer, or mixtures thereof, packaging, and instructions for use.

IV. DETAILED DESCRIPTION A. Overview

The invention encompasses compounds having formulae I-V and thecompositions and methods using these compounds in the treatment ofconditions in which modulation of the JAK pathway or inhibition of JAKkinases, particularly JAK3, may be therapeutically useful.

B. Definitions

As used herein, the following definitions shall apply unless otherwiseindicated.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—),isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—),sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl(CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

“Substituted alkyl” refers to an alkyl group having from 1 to 5hydrogens replaced with substituents selected from the group consistingof alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, alkynyl, substitutedalkynyl, guanidino, substituted guanidino, halo, hydroxy, heteroaryl,substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy,heteroarylthio, substituted heteroarylthio, heterocyclic, substitutedheterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, silyland trialkylsilyl wherein said substituents are defined herein. In someembodiments, the alkyl has 1 to 3 of the aforementioned groups. In otherembodiments, the alkyl has 1 to 2 of the aforementioned groups.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groupspreferably having from 1 to 5 and more preferably 1 to 3 carbon atomsthat are either straight-chained or branched. This term is exemplifiedby groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)—) or (—CH(CH₃)CH₂—) and thelike.

“Substituted alkylene” refers to an alkylene group having from 1 to 3hydrogens replaced with substituents selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl,nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic wherein said substituents are defined herein. In someembodiments, the alkylene has 1 to 2 of the aforementioned groups.

“Alkoxy” refers to the groups —O-alkyl, —O-alkenyl, and —O-alkynyl,wherein alkyl, alkenyl and alkynyl are as defined herein.

“Substituted alkoxy” refers to the groups —O-(substituted alkyl),—O-(substituted alkenyl), and —O-(substituted alkynyl), whereinsubstituted alkyl, substituted alkenyl, and substituted alkynyl are asdefined herein.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)— cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein. Acyl includes the“acetyl” group CH₃C(O)—.

“Acylamino” refers to the groups —NR²⁰C(O)alkyl, —NR²⁰C(O)substitutedalkyl, —NR²⁰C(O)cycloalkyl, —NR²⁰C(O)substituted cycloalkyl,—NR²⁰C(O)cycloalkenyl, —NR²⁰C(O)substituted cycloalkenyl,—NR²⁰C(O)alkenyl, —NR²⁰C(O)substituted alkenyl, —NR²⁰C(O)alkynyl,—NR²⁰C(O)substituted alkynyl, —NR²⁰C(O)aryl, —NR²⁰C(O)substituted aryl,—NR²⁰C(O)heteroaryl, —NR²⁰C(O)substituted heteroaryl,—NR²⁰C(O)heterocyclic, and —NR²⁰C(O)substituted heterocyclic wherein R²⁰is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, cycloalkenyl-C(O)O—, substitutedcycloalkenyl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—,heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O— wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR²¹R²² where R²¹ and R²² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-cycloalkenyl,—SO₂-substituted cylcoalkenyl, —SO₂-aryl, —SO₂-substituted aryl,—SO₂-heteroaryl, —SO₂-substituted heteroaryl, —SO₂-heterocyclic, and—SO₂-substituted heterocyclic and wherein R²¹ and R²² are optionallyjoined, together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that R²¹ and R²² are bothnot hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein. When R²¹ is hydrogen and R²² isalkyl, the substituted amino group is sometimes referred to herein as“alkylamino.” When R²¹ and R²² are alkyl, the substituted amino group issometimes referred to herein as “dialkylamino.” When referring to amonosubstituted amino, it is meant that either R²¹ or R²² is hydrogenbut not both. When referring to a disubstituted amino, it is meant thatneither R²¹ or R²² is hydrogen.

“Aminoacyl” refers to the group —C(O)NR²¹R²² where R²¹ and R²² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminothiocarbonyl” refers to the group —C(S)NR²¹R²² where R²¹ and R²²are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminocarbonylamino” refers to the group —NR²⁰C(O)NR²¹R²² where R²⁰ ishydrogen or alkyl and R²¹ and R²² are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminothiocarbonylamino” refers to the group —NR²⁰C(s)NR²¹R²² where R²⁰is hydrogen or alkyl and R²¹ and R²² are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminoacyloxy” refers to the group —O—C(O)NR²¹R²² where R²¹ and R²² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminosulfonyl” refers to the group —SO₂NR²¹R²² where R²¹ and R²² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminosulfonyloxy” refers to the group —O—SO₂NR²¹R²² where R²¹ and R²²are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminosulfonylamino” refers to the group —NR²⁰—SO₂NR²¹R²² where R²⁰ ishydrogen or alkyl and R²¹ and R²² are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkyenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkyenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the group —NR²¹SO₂R²² where R²¹ and R²² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the atoms bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Amidino” refers to the group —C(═NR²⁰)R²¹R²² where R²⁰, R²¹ and R²² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic (e.g., 1,2,3,4-tetrahydronaphthalene, and the like)provided that the point of attachment is at an aromatic carbon atom.Some representative examples include 1H-indenyl, 2,3-dihydro-1H-indenyl(indanyl), 1,2-dihydronaphthalenyl (tetralenyl), 1,4-dihydronaphthalenyl(tetralenyl), 1,2,3,4-tetrahydronaphthalenyl (tetralinyl),9,10-dihydrophenanthrenyl, 9H-fluorenyl, 4a,10-dihydroanthracenyl,4a,9,9a,10-tetrahydroanthracenyl, phenanthrenyl, anthracenyl,phenalenyl, etc. Preferred aryl groups include phenyl and naphthyl.

“Substituted aryl” refers to aryl groups having 1 to 5 hydrogensreplaced with substituents selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents aredefined herein. In some embodiments, the aryl has 1 to 3 of theaforementioned groups. In other embodiments, the aryl has 1 to 2 of theaforementioned groups. In some embodiments, aryl group having multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic (e.g., 1,2,3,4-tetrahydronaphthalene, and the like),the non-aromatic condensed ring may be optionally substituted with oxoin addition to the above defined substituents.

“Aryloxy” refers to the group —O-aryl, where aryl is as defined herein,that includes, by way of example, phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to the group —O-(substituted aryl) wheresubstituted aryl is as defined herein.

“Arylthio” refers to the group —S-aryl, where aryl is as defined herein.

“Substituted arylthio” refers to the group —S-(substituted aryl), wheresubstituted aryl is as defined herein.

“Alkenyl” refers to monovalent unsaturated hydrocarbyl groups havingfrom 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and havingat least 1 and preferably from 1 to 2 sites of unsaturation. Such groupsare exemplified by vinyl, allyl, but-3-en-1-yl, and the like.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents aredefined herein and with the proviso that any hydroxy substitution is notattached to a vinyl (unsaturated) carbon atom. In some embodiments, thealkenyl has 1 to 2 of the aforementioned groups.

“Alkenylene” refers to divalent unsaturated hydrocarbyl groups havingfrom 2 to 10 carbon atoms and preferably 2 to 6 carbon atoms and havingat least 1 and preferably from 1-2 sites of vinyl (double bond)unsaturation. The term “alkenylene” encompasses any and all combinationsof cis and trans isomers arising from the presence of unsaturation.

“Substituted alkenylene” refers to divalent alkenylene group having from1 to 3 substituents selected from the group consisting of alkyl,substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, amino,substituted amino, aminoacyl, aryl, substituted aryl, aryloxy,substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylesters, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic provided that anyhydroxyl substitution is not on a vinyl carbon atom. In someembodiments, the alkenylene has 1 to 2 of the aforementioned groups.

“Alkynyl” refers to monovalent unsaturated hydrocarbyl groups havingfrom 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and havingat least 1 and preferably from 1 to 2 sites of triple bond unsaturation.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents aredefined herein and with the proviso that any hydroxy substitution is notattached to an acetylenic carbon atom. In some embodiments, the alkynylhas 1 to 2 of the aforementioned groups.

“Carboxyl” or “carboxy” refers to —COOH or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl,—C(O)O— substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-cycloalkenyl, —C(O)O-substituted cycloalkenyl,—C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic,and —C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“(Carboxyl ester)amino” refers to the group —NR—C(O)O-alkyl, substituted—NR—C(O)O-alkyl, —NR—C(O)O-alkenyl, —NR—C(O)O-substituted alkenyl,—NR—C(O)O-alkynyl, —NR—C(O)O-substituted alkynyl, —NR—C(O)O-aryl,—NR—C(O)O-substituted aryl, —NR—C(O)O-cycloalkyl, —NR—C(O)O-substitutedcycloalkyl, —NR—C(O)O-cycloalkenyl, —NR—C(O)O-substituted cycloalkenyl,—NR—C(O)O-heteroaryl, —NR—C(O)O-substituted heteroaryl,—NR—C(O)O-heterocyclic, and —NR—C(O)O-substituted heterocyclic wherein Ris alkyl or hydrogen and alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

“(Carboxyl ester)oxy” refers to the group —O—C(O)O-alkyl, substituted—O—C(O)O-alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substituted alkenyl,—O—C(O)O-alkynyl, —O—C(O)O-substituted alkynyl, —O—C(O)O-aryl,—O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl, —O—C(O)O-substitutedcycloalkyl, —O—C(O)O-cycloalkenyl, —O—C(O)O-substituted cycloalkenyl,—O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl,—O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Carbonate ester” refers to the groups —OC(O)O-alkyl, —OC(O)O—substituted alkyl, —OC(O)O-alkenyl, —OC(O)O-substituted alkenyl,—OC(O)O-alkynyl, —OC(O)O-substituted alkynyl, —OC(O)O-aryl,—OC(O)O-substituted aryl, —OC(O)O-cycloalkyl, —OC(O)O-substitutedcycloalkyl, —OC(O)O-cycloalkenyl, —OC(O)O-substituted cycloalkenyl,—OC(O)O-heteroaryl, —OC(O)O-substituted heteroaryl,—OC(O)O-heterocyclic, and —OC(O)O-substituted heterocyclic whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Cyano” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. Examples of suitable cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyland the like.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to10 carbon atoms having single or multiple cyclic rings and having atleast one >C═C< ring unsaturation and preferably from 1 to 2 sitesof >C═C< ring unsaturation.

“Substituted cycloalkyl” and “substituted cycloalkenyl” refers to acycloalkyl or cycloalkenyl group having from 1 to 5 substituentsselected from the group consisting of oxo, thioxo, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substitutedamino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents aredefined herein. In some embodiments, the cycloalkyl or cycloalkenyl has1 to 3 of the aforementioned groups.

“Cycloalkoxy” refers to —O-cycloalkyl.

“Substituted cycloalkoxy” refers to —O-(substituted cycloalkyl).

“Cycloalkylthio” refers to —S-cycloalkyl.

“Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl).

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Substituted cycloalkenyloxy” refers to —O-(substituted cycloalkenyl).

“Cycloalkenylthio” refers to —S-cycloalkenyl.

“Substituted cycloalkenylthio” refers to —S-(substituted cycloalkenyl).

“Guanidino” refers to the group —NHC(═NH)NH₂.

“Substituted guanidino” refers to —NRC(═NR)N(R)₂ where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and two R groupsattached to a common guanidino nitrogen atom are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, provided that at least one R is nothydrogen, and wherein said substituents are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is fluoro or chloro.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 5 to 15 ring atomsincluding 1 to 4 heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur. Such heteroaryl groups can have a singlering (e.g., pyridinyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl) wherein the condensed rings may or may notbe aromatic and/or contain a heteroatom provided that the point ofattachment is through an atom of the aromatic heteroaryl group. In oneembodiment, the nitrogen and/or the sulfur ring atom(s) of theheteroaryl group are optionally oxidized to provide for the N-oxide(N→O), sulfinyl, or sulfonyl moieties. In preferred embodiments, theheteroaryl group is a 5-14 membered heteroaryl, with 5-10 memberedheteroaryl being particularly preferred. Preferred heteroaryls includepyridinyl, pyrimidinyl, pyrazinyl, pyridizinyl, triazine, pyrrolyl,indolyl, thiophenyl, and furanyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 5 substituents selected from the groupconsisting of the same group of substituents defined for substitutedaryl. In some embodiments, the heteroaryl has 1 to 3 of theaforementioned groups. In other embodiments, the heteroaryl has 1 to 2of the aforementioned groups. In some embodiments, heteroaryl grouphaving multiple condensed rings which condensed rings may or may not bearomatic, the non-aromatic condensed ring may be optionally substitutedwith oxo in addition to the same group of substituents defined forsubstituted aryl.

“Heteroaryloxy” refers to —O-heteroaryl.

“Substituted heteroaryloxy” refers to the group —O-(substitutedheteroaryl).

“Heteroarylthio” refers to the group —S-heteroaryl.

“Substituted heteroarylthio” refers to the group —S-(substitutedheteroaryl).

“Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl”refers to a saturated or unsaturated group having a single ring ormultiple condensed rings, including fused bridged and spiro ringsystems, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selectedfrom the group consisting of nitrogen, sulfur or oxygen within the ringwherein, in fused ring systems, one or more the rings can be cycloalkyl,aryl or heteroaryl provided that the point of attachment is through thenon-aromatic ring. In one embodiment, the nitrogen and/or sulfur atom(s)of the heterocyclic group are optionally oxidized to provide for theN-oxide, sulfinyl, sulfonyl moieties.

“Substituted heterocyclic” or “substituted heterocycloalkyl” or“substituted heterocyclyl” refers to heterocyclyl groups that aresubstituted with from 1 to 5 of the same substituents as defined forsubstituted cycloalkyl. In some embodiments, the heterocyclyl has 1 to 3of the aforementioned groups.

“Heterocyclyloxy” refers to the group —O-heterocycyl.

“Substituted heterocyclyloxy” refers to the group —O-(substitutedheterocycyl).

“Heterocyclylthio” refers to the group —S-heterocycyl.

“Substituted heterocyclylthio” refers to the group —S-(substitutedheterocycyl).

Examples of heterocycle and heteroaryls include, but are not limited to,acridine, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

Typical heteroaryl groups include, but are not limited to, groupsderived from acridine, azetidine, benzimidazole, benzisoxazole,benzo[b]thiophene, benzodiaxole, benzodioxan, benzofuran, benzopyrone,benzothiadiazole, benzothiazole, benzotriazole, benzoxazine,benzoxazole, benzoxazoline, carbazole, carboline, β-carboline, chromane,chromene, cinnoline, dihydroindole, 1,1-dioxothiomorpholinyl, furan,imidazole, imidazolidine, imidazoline, indazole, indole, indoline,indolizine, isobenzofuran, isochromene, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, morpholinyl, naphthylpyridine,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,phenanthroline, phenazine, phenothiazine, phenoxazine, phthalazine,phthalimide, piperazine, piperidine, pteridine, pteridine, purine,pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolidone, pyrrolizine, quinazoline, quinoline, quinolizine,quinoxaline, 4,5,6,7-tetrahydrobenzo[b]thiophene, tetrahydrofuranyl,1,2,3,4-tetrahydroisoquinoline, tetrazole, thiadiazole, thiazole,thiazolidine, thiomorpholinyl (also referred to as thiamorpholinyl),thiophene, triazole, xanthene, and the like, as well as the varioushydro isomers thereof.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O).

“Spirocycloalkyl” refers to cyclic groups from 3 to 10 carbon atomshaving a cycloalkyl ring with a spiro union (the union formed by analkylene or substituted alkylene bridge wherein both ends are bonded toa single atom in a chain or part of another ring system) as exemplifiedby the following structure:

“Sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cycloalkyl, —SO₂-cycloalkenyl, —SO₂-substitutedcylcoalkenyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, —SO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein. Sulfonyl includes groups such asmethyl-SO₂—, phenyl-SO₂—, and 4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, —OSO₂-substituted alkyl,—OSO₂-alkenyl, —OSO₂-substituted alkenyl, —OSO₂-cycloalkyl,—OSO₂-substituted cycloalkyl, —OSO₂-cycloalkenyl, —OSO₂-substitutedcylcoalkenyl, —OSO₂-aryl, —OSO₂-substituted aryl, —OSO₂-heteroaryl,—OSO₂-substituted heteroaryl, —OSO₂-heterocyclic, —OSO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Thioacyl” refers to the groups H—C(S)—, alkyl-C(S)—, substitutedalkyl-C(S)—, alkenyl-C(S)—, substituted alkenyl-C(S)—, alkynyl-C(S)—,substituted alkynyl-C(S)—, cycloalkyl-C(S)—, substitutedcycloalkyl-C(S)—, cycloalkenyl-C(S)—, substituted cycloalkenyl-C(S)—,aryl-C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—, substitutedheteroaryl-C(S)—, heterocyclic-C(S)—, and substitutedheterocyclic-C(S)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thioxo” refers to the atom (═S).

“Alkylthio” refers to the group —S-alkyl wherein alkyl is as definedherein.

“Silyl” refers to the group —SiH₃. “Trialkylsilyl” refers to the group—SiR₃, wherein each R is independently alkyl or substituted alkyl.

“Substituted alkylthio” refers to the group —S-(substituted alkyl)wherein substituted alkyl is as defined herein.

“Stereoisomer” or “stereoisomers” refer to compounds that differ in thechirality of one or more stereocenters. Stereoisomers includeenantiomers and diastereomers.

“Tautomer” refer to alternate forms of a molecule that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a ring atomattached to both a ring —NH— moiety and a ring ═N— moeity such aspyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

“Patient” refers to humans and non-human animals.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound, which salts are derived from a variety of organicand inorganic counter ions well known in the art and include, by way ofexample only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate and the like.

“Prodrug” refers to a derivative of an active 2,4-pyrimidinediaminecompound (drug) that may require a transformation under the conditionsof use, such as within the body, to release the active2,4-pyrimidinediamine drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. Prodrugs are typically obtained by masking one or more functionalgroups in an active 2,4-pyrimidinediamine drug believed to be in partrequired for activity with a progroup (defined below) to form apromoiety which undergoes a transformation, such as cleavage, under thespecified conditions of use to release the functional group, and hencethe active 2,4-pyrimidinediamine drug. The cleavage of the promoiety mayproceed spontaneously, such as by way of a hydrolysis reaction, or itmay be catalyzed or induced by another agent, such as by an enzyme, bylight, by acid or base, or by a change of or exposure to a physical orenvironmental parameter, such as a change of temperature. The agent maybe endogenous to the conditions of use, such as an enzyme present in thecells to which the prodrug is administered or the acidic conditions ofthe stomach, or it may be supplied exogenously.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active 2,4-pyrimidinediamine drug to form apromoiety, converts the drug into a prodrug. Progroups are typicallyattached to the functional group of the drug via bonds that arecleavable under specified conditions of use. Thus, a progroup is thatportion of a promoiety that cleaves to release the functional groupunder the specified conditions of use. As a specific example, an amidepromoiety of the formula —NH—C(O)CH₃ comprises the progroup —C(O)CH₃.Even more specifically, one or more sulfonamide groups of a2,4-pyrimidinediamine compound of the invention protected by an acylgroup to for —SO₂N(H)C(O)CH₃ and the like.

“Pharmaceutically effective amount” or “therapeutically effectiveamount” refers to an amount of a compound sufficient to treat aspecified disorder or disease or one or more of its symptoms and/or toprevent the occurrence of the disease or disorder. In reference totumorigenic proliferative disorders, a pharmaceutically ortherapeutically effective amount comprises an amount sufficient to,among other things, cause the tumor to shrink or to decrease the growthrate of the tumor.

“Solvate” refers to a compound formed by combination of solventmolecules with molecules or ions of the solute. The solvent can beeither an organic or an inorganic compound. Some examples of solventsinclude but are not limited to, methanol, N,N-dimethylformamide,tetrahydrofuran, dimethylsulfoxide, water, etc.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycabonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted by a substituted aryl group etc.) are notintended for inclusion herein. In such cases, the maximum number of suchsubstitutions is three. For example, serial substitutions of substitutedaryl groups are limited to -substituted aryl-(substitutedaryl)-substituted aryl.

Similarly, it is understood that the above definitions are not intendedto include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluoro groups). Such impermissible substitution patterns areeasily recognized by a person having ordinary skill in the art.

C. Compounds of the Invention

This invention provides novel 2,4-substituted pyrimidinediaminecompounds, prodrugs of the compounds, methods of making the compoundsand methods of using these compounds in the treatment of conditions inwhich targeting of the JAK pathway or inhibition of JAK kinases,particularly JAK3, may be therapeutically useful. These conditionsinclude, but are not limited to, debilitating and fatal diseases anddisorders that affect both children and adults, for example, oncologicaldiseases, such as leukemia, including e.g., childhood leukemia,lymphoma, autoimmune conditions, such as transplant rejection, and theother conditions described herein. Given the severity of and sufferingcaused by these conditions, it is vital that new treatments aredeveloped to treat these conditions.

In one embodiment, the present invention provides a compound of formulaI, prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   R is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl and substituted cycloalkyl;    -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   Y is selected from the group consisting of a bond, —NR⁷—,        —C(O)NR⁷—, —NR⁷C(O)—, —NR⁷C(O)O—, —OC(O)NR⁷—, —NR⁷C(O)NR⁷—,        oxygen and sulfur, where R⁷ is independently hydrogen, alkyl or        substituted alkyl;    -   alk is a bond or a straight or branched chain alkylene group,        wherein when alk and Y each are a bond then R¹ is attached to        ring A by a single covalent bond;    -   R¹ is selected from the group consisting of cyano, acylamino,        aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester,        carboxyl ester oxy, heteroaryl, substituted heteroaryl,        heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and        aminocarbonylamino; or        -   R¹-alk-Y— is R¹⁰—C(O)—S-alk-C(O)—, wherein alk is as defined            herein and R¹⁰ is alkyl or substituted alkyl; or        -   R¹-alk-Y— is R¹¹R¹²NS(O)₂—, wherein R¹¹ and R¹²            independently are alkyl or substituted alkyl;    -   p is 0, 1, 2 or 3 when ring A is a single ring or p is 0, 1, 2,        3, 4, or 5 when ring A comprises multiple rings;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro, and halo, or two of R² on the        same carbon form an oxo (═O);    -   Z¹, Z², and Z³ each independently is carbon or nitrogen, wherein        if Z¹ is nitrogen then Z² and Z³ are carbon, if Z² is nitrogen        then Z¹ and Z³ are carbon, and if Z³ is nitrogen then Z¹ and Z²        are carbon, wherein if Z¹, Z², or Z³ is nitrogen then SO₂R⁴R⁵ is        not attached to the nitrogen;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group; or        -   when q is 1, 2 or 3, R⁵ can be joined with one R³ group            bound alpha thereto, to form a fused ring as illustrated in            formula II:

-   -   -   wherein W is selected from the group consisting of C₁-C₃            alkylene, substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and            substituted C₂-C₃ alkenylene wherein one or more of the            carbon atoms have been replaced with a moiety selected from            oxygen, sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is            selected from the group consisting of hydrogen and alkyl or            is a bond participating in a —N═C< site of unsaturation;            provided that:

    -   when alk is a bond and Y is a bond, then R¹ is not cyano,        carboxyl, carboxyl ester, or aminoacarbonylamino;

    -   when alk is —CH₂—, Y is oxygen and R¹ is phenyl, ring A is not        cycloalkyl;

    -   when alk is a bond, Y is a bond, ring A is phenyl, then R¹ is        not heterocyclic, substituted heterocyclic or aminoacyloxy;

    -   when Y or R¹-alk-Y— provide for direct linkage of either        —NR⁷C(O)O— or —NR⁷C(O)NR⁷— to ring A, then R⁷ is hydrogen; and

    -   when Y is —C(O)NR⁷—, —NR⁷C(O)—, —OC(O)NR⁷—, —NR⁷C(O)O— or        —NR⁷C(O)NR⁷— and alk is a bond, then R¹ is not acyl, acylamino,        aminoacyl or aminocarbonylamino.

When R⁴ or R⁵ is a divalent counterion selected from the groupconsisting of Ca²⁺, Mg²+, and Ba²⁺, the nitrogen of sulfonamide wouldcarry a negative charge, but the counterion would be associated with twoparent molecular ions, or alternatively, there might be another group onthe ring that can provide another anion. For example, a chloride orsimilar anions can be used to satisfy the charge of the divalent metal(such as Mg⁺⁺Cl⁻ etc.).

Certain embodiments of the invention provide compounds having thestructure of formula IA, prodrugs, solvates, or pharmaceuticallyacceptable salts thereof:

wherein:

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   R is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl and substituted cycloalkyl;    -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   alk is a bond or a straight or branched chain alkylene group;    -   R¹ is selected from the group consisting of cyano, acylamino,        aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester,        carboxyl ester oxy, heteroaryl, substituted heteroaryl,        heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and        aminocarbonylamino;    -   p is 0, 1, 2 or 3 when ring A is a single ring or p is 0, 1, 2,        3, 4, or 5 when ring A comprises multiple rings;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group; or        -   when q is 1, 2 or 3, R⁵ can be joined with one R³ group            bound alpha thereto, to form a fused ring as illustrated in            formula IIA:

-   -   -   wherein W is selected from the group consisting of C₁-C₃            alkylene, substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and            substituted C₂-C₃ alkenylene wherein one or more of the            carbon atoms have been replaced with a moiety selected from            oxygen, sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is            selected from the group consisting of hydrogen and alkyl or            is a bond participating in a —N═C< site of unsaturation.

Preferably ring A is phenyl.

Other embodiments include compounds having the structure of formula IB,and prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   alk is a bond or a straight or branched chain alkylene group;    -   R¹ is selected from the group consisting of cyano, acylamino,        aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester,        carboxyl ester oxy, heteroaryl, substituted heteroaryl,        heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and        aminocarbonylamino;    -   p is 0, 1, 2 or 3 when ring A is a single ring or p is 0, 1, 2,        3, 4, or 5 when ring A comprises multiple rings;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group.

Yet other embodiments provide compounds having the structure of formulaIC, prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   alk is a bond or a straight or branched chain alkylene group;    -   R¹ is selected from the group consisting of cyano, acylamino,        aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester,        carboxyl ester oxy, heteroaryl, substituted heteroaryl,        heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and        aminocarbonylamino;    -   p is 0, 1, 2 or 3 when ring A is a single ring or p is 0, 1, 2,        3, 4, or 5 when ring A comprises multiple rings;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group.

Other embodiments include compounds having the structure of formula ID,prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   alk is a bond or a straight or branched chain alkylene group;    -   R¹ is selected from the group consisting of cyano, acylamino,        aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester,        carboxyl ester oxy, heteroaryl, substituted heteroaryl,        heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and        aminocarbonylamino;    -   p is 0, 1, 2 or 3 when ring A is a single ring or p is 0, 1, 2,        3, 4, or 5 when ring A comprises multiple rings;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro, and halo, or two of R² on the        same carno form an oxo (═O);    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula IE, prodrugs, solvates, orpharmaceutically acceptable salts thereof:

wherein:

-   -   alk is a bond or a straight or branched chain alkylene group;    -   R¹ is selected from the group consisting of cyano, acylamino,        aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester,        carboxyl ester oxy, heteroaryl, substituted heteroaryl,        heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and        aminocarbonylamino;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro, and halo, or two of R² on the        same carno form an oxo (═O);    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula III, prodrugs, solvates, orpharmaceutically acceptable salts thereof:

wherein:

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   R is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl and substituted cycloalkyl;    -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, sulfonyl, oxo, nitro and halo;    -   Z¹, Z², and Z³ each independently is carbon or nitrogen, wherein        if Z¹ is nitrogen then Z² and Z³ are carbon, if Z² is nitrogen        then Z¹ and Z³ are carbon, and if Z³ is nitrogen then Z¹ and Z²        are carbon, wherein if Z¹, Z², or Z³ is nitrogen then SO₂R⁴R⁵ is        not attached to the nitrogen;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group; or        -   when q is 1, 2 or 3, R⁵ can be joined with one R³ group            bound alpha thereto, to form a fused ring as illustrated in            formula IV:

-   -   -   wherein W is selected from the group consisting of C₁-C₃            alkylene, substituted

C₁-C₃ alkylene, C₂-C₃ alkenylene and substituted C₂-C₃ alkenylenewherein one or more of the carbon atoms have been replaced with a moietyselected from oxygen, sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ isselected from the group consisting of hydrogen and alkyl or is a bondparticipating in a —N═C< site of unsaturation;

provided that:

-   -   if p=0, then X is not bromo;    -   if ring A is cycloalkyl, then X is not bromo;    -   if p=2 and each of R² is methoxy, halo, trihalomethyl or        trihalomethoxy, then R⁴ and R⁵ are not one hydrogen and one        methyl;    -   if p=2 and R² is fluoro and methyl, then R is not substituted        alkenyl; and    -   if ring A is phenyl, p=1 and R² is chloro, then R⁴ and R⁵ are        not one hydrogen and one methyl.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula IIIA, prodrugs, solvates, orpharmaceutically acceptable salts thereof:

wherein:

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or    -   R⁴ and R⁵ together with the nitrogen atom bound thereto, form a        heterocyclic or substituted heterocyclic group each R²        independently is selected from the group consisting of alkyl,        substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula IIIA, prodrugs, solvates, orpharmaceutically acceptable salts thereof wherein:

-   -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;

X is fluoro or methyl; and

-   -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl and acyl; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula IIIA, prodrugs, solvates, orpharmaceutically acceptable salts thereof wherein:

-   -   ring A is phenyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;

X is fluoro or methyl; and

-   -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl and acyl; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula IVA, prodrugs, solvates, orpharmaceutically acceptable salts thereof:

wherein:

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, sulfonyl, oxo, nitro and halo;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ is independently selected from the group consisting of        hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺ is a        metal counterion selected from the group consisting of K⁺, Na⁺,        Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴ is N⁻; or        -   R⁴ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴ is N⁻;    -   q−1 is 0, 1 or 2; and    -   W is selected from the group consisting of C₁-C₃ alkylene,        substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and substituted        C₂-C₃ alkenylene wherein one or more of the carbon atoms have        been replaced with a moiety selected from oxygen, sulfur, S(O),        S(O)₂, C(O), or NR⁸ where R⁸ is selected from the group        consisting of hydrogen and alkyl or is a bond participating in a        —N═C< site of unsaturation;        provided that:    -   if p=0, then X is not bromo;    -   if ring A is cycloalkyl, then X is not bromo;    -   if p=2 and each of R² is methoxy, halo, trihalomethyl or        trihalomethoxy, then R⁴ and R⁵ are not one hydrogen and one        methyl;    -   if p=2 and R² is fluoro and methyl, then R is not substituted        alkenyl; and    -   if ring A is phenyl, p=1 and R² is chloro, then R⁴ and R⁵ are        not one hydrogen and one methyl.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula IVA, prodrugs, solvates, orpharmaceutically acceptable salts thereof wherein:

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   ring A is phenyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, sulfonyl, oxo, nitro and halo;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ is independently selected from the group consisting of        hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺ is a        metal counterion selected from the group consisting of K⁺, Na⁺,        Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴ is N⁻; or        -   R⁴ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴ is N⁻;    -   q−1 is 0, 1 or 2; and    -   W is selected from the group consisting of C₁-C₃ alkylene,        substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and substituted        C₂-C₃ alkenylene wherein one or more of the carbon atoms have        been replaced with a moiety selected from oxygen, sulfur, S(O),        S(O)₂, C(O), or NR⁸ where R⁸ is selected from the group        consisting of hydrogen and alkyl or is a bond participating in a        —N═C< site of unsaturation;        provided that:    -   if p=0, then X is not bromo;    -   if ring A is cycloalkyl, then X is not bromo;    -   if p=2 and each of R² is methoxy, halo, trihalomethyl or        trihalomethoxy, then R⁴ and R⁵ are not one hydrogen and one        methyl;    -   if p=2 and R² is fluoro and methyl, then R is not substituted        alkenyl; and    -   if ring A is phenyl, p=1 and R² is chloro, then R⁴ and R⁵ are        not one hydrogen and one methyl.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula IIIB, prodrugs, solvates, orpharmaceutically acceptable salts thereof:

wherein:

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula IIIB, prodrugs, solvates, orpharmaceutically acceptable salts thereof wherein:

-   -   X is fluoro or methyl;    -   ring A is selected from the group consisting of aryl,        heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic, wherein        ring A is not indolyl or benzimidazolyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl and acyl; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula IIIB, prodrugs, solvates, orpharmaceutically acceptable salts thereof wherein:

-   -   X is fluoro or methyl;    -   ring A is phenyl;    -   p is 0, 1, 2 or 3;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro and halo;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl and acyl; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula V, prodrugs, solvates, orpharmaceutically acceptable salts thereof wherein:

wherein:

-   -   X is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, amino, substituted amino,        carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl and substituted alkynyl;    -   R is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl and substituted cycloalkyl;    -   Z¹, Z², and Z³ each independently is carbon or nitrogen, wherein        if Z¹ is nitrogen then Z² and Z³ are carbon, if Z² is nitrogen        then Z¹ and Z³ are carbon, and if Z³ is nitrogen then Z¹ and Z²        are carbon, wherein if Z¹, Z², or Z³ is nitrogen then SO₂R⁴R⁵ is        not attached to the nitrogen;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group; or    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl and acyl; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group;    -   R⁷ is selected from the group consisting of hydrogen, alkyl or        substituted alkyl; and    -   V is selected from the group consisting of C₁-C₃ alkylene,        substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and substituted        C₂-C₃ alkenylene wherein one or more of the carbon atoms have        been replaced with a heteroatom selected from oxygen, sulfur,        S(O), S(O)₂, or NR⁸ where R⁸ is selected from the group        consisting of hydrogen and alkyl or is a bond participating in a        —N═C< site of unsaturation.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula VA, prodrugs, solvates, orpharmaceutically acceptable salts thereof wherein:

wherein:

-   -   X is fluoro or methyl;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group; or    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl and acyl; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group;    -   R⁷ is selected from the group consisting of hydrogen, alkyl or        substituted alkyl; and    -   V is selected from the group consisting of C₁-C₃ alkylene,        substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and substituted        C₂-C₃ alkenylene wherein one or more of the carbon atoms have        been replaced with a heteroatom selected from oxygen, sulfur,        S(O), S(O)₂, or NR⁸ where R⁸ is selected from the group        consisting of hydrogen and alkyl or is a bond participating in a        —N═C< site of unsaturation.

Yet other preferred embodiments of the invention provide compoundshaving the structure of formula VB, prodrugs, solvates, orpharmaceutically acceptable salts thereof wherein:

wherein:

-   -   X is fluoro or methyl;    -   q is 0, 1, 2 or 3;    -   each R³ independently is selected from the group consisting of        hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl or substituted cycloalkyl, halo, heterocyclic and        substituted heterocyclic;    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺        is a metal counterion selected from the group consisting of K⁺,        Na⁺, Li⁺ or ⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the        nitrogen of SO²NR⁴R⁵ is N⁻; or        -   R⁴ or R⁵ is a divalent counterion selected from the group            consisting of Ca²⁺, Mg²+, and Ba²⁺, and the nitrogen of            SO₂NR⁴R⁵ is N⁻; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group; or    -   R⁴ and R⁵ independently are selected from the group consisting        of hydrogen, alkyl, substituted alkyl and acyl; or        -   R⁴ and R⁵ together with the nitrogen atom bound thereto,            form a heterocyclic or substituted heterocyclic group;    -   R⁷ is selected from the group consisting of hydrogen, alkyl or        substituted alkyl; and    -   V is selected from the group consisting of C₁-C₃ alkylene,        substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and substituted        C₂-C₃ alkenylene wherein one or more of the carbon atoms have        been replaced with a heteroatom selected from oxygen, sulfur,        S(O), S(O)₂, or NR⁸ where R⁸ is selected from the group        consisting of hydrogen and alkyl or is a bond participating in a        —N═C< site of unsaturation.

Those of skill in the art will appreciate that the 2,4-substitutedpyrimidinediamine compounds described herein may include functionalgroups that can be masked with progroups to create prodrugs. Suchprodrugs are usually, but need not be, pharmacologically inactive untilconverted into their active drug form. Indeed, many of the2,4-substituted pyrimidinediamine compounds described in this inventioninclude promoieties that are hydrolyzable or otherwise cleavable underconditions of use. For example, ester groups commonly undergoacid-catalyzed hydrolysis to yield the parent carboxylic acid whenexposed to the acidic conditions of the stomach, or base-catalyzedhydrolysis when exposed to the basic conditions of the intestine orblood. Thus, when administered to a subject orally, 2,4-substitutedpyrimidinediamine compounds that include ester moieties may beconsidered prodrugs of their corresponding carboxylic acid, regardlessof whether the ester form is pharmacologically active.

The mechanism by which the progroup(s) metabolizes is not critical, andcan be caused by, for example, hydrolysis under the acidic conditions ofthe stomach, as described above, and/or by enzymes present in thedigestive tract and/or tissues or organs of the body. Indeed, theprogroup(s) can be selected to metabolize at a particular site withinthe body. For example, many esters are cleaved under the acidicconditions found in the stomach. Prodrugs designed to cleave chemicallyin the stomach to the active 2,4-substituted pyrimidinediamine, canemploy progroups including such esters. Alternatively, the progroups maybe designed to metabolize in the presence of enzymes such as esterases,amidases, lipolases, phosphatases including ATPases and kinase etc.Progroups including linkages capable of metabolizing in vivo arewell-known, and include, by way of example and not limitation, ethers,thioethers, silylethers, silylthioethers, esters, thioesters,carbonates, thiocarbonates, carbamates, thiocarbamates, ureas,thioureas, carboxamides, etc. In some instances, a “precursor” groupthat is oxidized by oxidative enzymes such as, for example, cytochromeP450 of the liver, to a metabolizable group, can be selected.

In the prodrugs, any available functional moiety may be masked with aprogroup to yield a prodrug. Functional groups within the2,4-substituted pyrimidinediamine compounds that may be masked withprogroups for inclusion in a promoiety include, but are not limited to,amines (primary and secondary), hydroxyls, sulfanyls (thiols),carboxyls, etc. A wide variety of progroups, as well as the resultantpromoieties, suitable for masking functional groups in active2,4-pyrimidinediamine compounds to yield prodrugs are well-known in theart. For example, a hydroxyl functional group may be masked as asulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivoto provide the hydroxyl group. An amino functional group may be maskedas an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenylpromoiety, which may be hydrolyzed in vivo to provide the amino group. Acarboxyl group may be masked as an ester (including silyl esters andthioesters), amide or hydrazide promoiety, which may be hydrolyzed invivo to provide the carboxyl group. Other specific examples of suitableprogroups and their respective promoieties will be apparent to those ofskill in the art. All of these progroups, alone or in combinations, maybe included in the prodrugs.

In some embodiments of the 2,4-substituted pyrimidinediamine compoundsand methods of using the compounds, the progroup(s) can be attached toany available primary or secondary amine, including, for example, the N2nitrogen atom of the 2,4-pyrimidinediamine moiety, the N4 nitrogen atomof the 2,4-pyrimidinediamine moiety, and/or a primary or secondarynitrogen atom included in a substituent on the 2,4-pyrimidinediaminecompound.

In particular embodiments of the 2,4-substituted pyrimidinediaminecompounds and methods of using the compounds, the prodrugs describedherein are 2,4-substituted pyrimidinediamine compounds that aresubstituted at the N4 nitrogen of the 2,4-pyrimidinediamine moiety witha substituted or unsubstituted nitrogen-containing bicyclic ring thatincludes at least one progroup at one or more of: the nitrogen atom(s)of the bicyclic ring, the N2 nitrogen of the 2,4-pyrimidinediaminemoiety and/or the N4 nitrogen of the 2,4-pyrimidinediamine moiety.

As noted above, the identity of the progroup is not critical, providedthat it can be metabolized under the desired conditions of use, forexample under the acidic conditions found in the stomach and/or byenzymes found in vivo, to yield a the biologically active group, e.g.,the 2,4-substituted pyrimidinediamines as described herein. Thus,skilled artisans will appreciate that the progroup can comprisevirtually any known or later-discovered hydroxyl, amine or thiolprotecting group. Non-limiting examples of suitable protecting groupscan be found, for example, in Protective Groups in Organic Synthesis,Greene & Wuts, 2nd Ed., John Wiley & Sons, New York, 1991 (especiallypages 10-142 (alcohols, 277-308 (thiols) and 309-405 (amines) thedisclosure of which is incorporated herein by reference).

Additionally, the identity of the progroup(s) can also be selected so asto impart the prodrug with desirable characteristics. For example,lipophilic groups can be used to decrease water solubility andhydrophilic groups can be used to increase water solubility. In thisway, prodrugs specifically tailored for selected modes of administrationcan be obtained. The progroup can also be designed to impart the prodrugwith other properties, such as, for example, improved passive intestinalabsorption, improved transport-mediated intestinal absorption,protection against fast metabolism (slow-release prodrugs),tissue-selective delivery, passive enrichment in target tissues,targeting-specific transporters, etc. Groups capable of impartingprodrugs with these characteristics are well-known, and are described,for example, in Ettmayer et al., 2004, J. Med. Chem. 47(10):2393-2404,the disclosure of which is incorporated by reference. All of the variousgroups described in these references can be utilized in the prodrugsdescribed herein.

As noted above, progroup(s) may also be selected to increase the watersolubility of the prodrug as compared to the active drug. Thus theprogroup(s) may include or may be a group(s) suitable for imparting drugmolecules with improved water solubility. Such groups are well-known,and include, by way of example and not limitation, hydrophilic groupssuch as alkyl, aryl, arylalkyl, or cycloheteroalkyl groups substitutedwith one or more of an amine, alcohol, a carboxylic acid, a phosphorousacid, a sulfoxide, a sugar, an amino acid, a thiol, a polyol, an ether,a thioether and a quaternary amine salt.

The suitability of any particular progroup for a desired mode ofadministration can be confirmed in biochemical assays. For example, if aprodrug is to be administered by injection into a particular tissue ororgan, and the identities of the various enzyme(s) expressed in thetissue or organ are known, the particular prodrug can be tested formetabolism in biochemical assays with the isolated enzyme(s).Alternatively, the particular prodrug can be tested for metabolism tothe active 2,4-substituted pyrimidinediamine compound with tissue and/ororgan extracts. Using tissue and/or organ extracts can be of particularconvenience when the identity(ies) of the enzymes expressed in thetarget tissues or organs are unknown, or in instances when the isolatedenzymes are not conveniently available. Skilled artisans will be able toreadily select progroups having metabolic properties (such as kinetics)suitable for particular applications using such in vitro tests. Ofcourse, specific prodrugs could also be tested for suitable metabolismin in vitro animal models.

Numerous references teach the use and synthesis of prodrugs, including,for example, Ettmayer et al., ibid and Bungaard et al., (1989) J. Med.Chem. 32(12): 2503-2507. Additionally, the preparation and use ofprodrugs of 2,4-pyrimidinediamines is specifically taught in U.S.Provisional Patent Application 60/654,620, filed Feb. 18, 2005, entitled“Pyrimidinediamine Prodrugs and their Uses,” the disclosure of which ishereby incorporated by reference in its entirety.

One of ordinary skill in the art will appreciate that many of thecompounds and prodrugs thereof, as well as the various compound speciesspecifically described and/or illustrated herein, may exhibit thephenomena of tautomerism, conformational isomerism, geometric isomerismand/or optical isomerism. For example, the compounds and prodrugs of theinvention may include one or more chiral centers and/or double bonds andas a consequence may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers and diasteromers and mixturesthereof, such as racemic mixtures. As another example, the compounds andprodrugs of the invention may exist in several tautomeric forms,including the enol form, the keto form and mixtures thereof. As thevarious compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric or geometricisomeric forms, it should be understood that the invention encompassesany tautomeric, conformational isomeric, optical isomeric and/orgeometric isomeric forms of the compounds or prodrugs having one or moreof the utilities described herein, as well as mixtures of these variousdifferent isomeric forms. Atropisomers are stereoisomers resulting fromhindered rotation about single bonds where the barrier to rotation ishigh enough to allow for the isolation of the conformers (Eliel, E. L.;Wilen, S. H. Stereochemistry of Organic Compounds; Wiley & Sons: NewYork, 1994; Chapter 14). Atropisomerism is significant because itintroduces an element of chirality in the absence of stereogenic atoms.The invention is meant to encompass atropisomers, for example in casesof limited rotation around bonds between the 2,4-pyrimidinediamine corestructure and groups attached thereto or for example around bondsbetween the A ring or the ring bearing Z¹⁻³ and respective groupsattached thereto. It is intended that the compounds encompassed hereinare, with the exception of forms of isomerism, chemically stable andable to be isolated.

Depending upon the nature of the various substituents, the2,4-pyrimidinediamine compounds and prodrugs of the invention may be inthe form of salts. Such salts include salts suitable for pharmaceuticaluses (“pharmaceutically-acceptable salts”), salts suitable forveterinary uses, etc. Such salts may be derived from acids or bases, asis well-known in the art.

In one embodiment, the salt is a pharmaceutically acceptable salt.Generally, pharmaceutically acceptable salts are those salts that retainsubstantially one or more of the desired pharmacological activities ofthe parent compound and which are suitable for administration to humans.Pharmaceutically acceptable salts include acid addition salts formedwith inorganic acids or organic acids. Inorganic acids suitable forforming pharmaceutically acceptable acid addition salts include, by wayof example and not limitation, hydrohalide acids (e.g., hydrochloricacid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids suitable for formingpharmaceutically acceptable acid addition salts include, by way ofexample and not limitation, acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, palmiticacid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid,mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid,ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonicacid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, etc.),4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like.

Pharmaceutically acceptable salts also include salts formed when anacidic proton present in the parent compound is either replaced by ametal ion (e.g., an alkali metal ion, an alkaline earth metal ion or analuminum ion) or coordinates with an organic base (e.g., ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, morpholine,piperidine, dimethylamine, diethylamine, triethylamine, ammonia, etc.).

The 2,4-pyrimidinediamine compounds and prodrugs thereof, as well as thesalts thereof, may also be in the form of hydrates, solvates andN-oxides, as are well-known in the art.

In another embodiment, this invention provides a compound, orstereoisomer, tautomer, prodrug, solvate, or pharmaceutically acceptablesalt thereof, selected from Tables I-XI.

TABLE I

# R¹— -alk-Y— (R²)_(p) R X Z (R³)_(q) SO₂NR⁴R⁵ I-1 3-NC— —CH₂—O— 4,5-di-H F C — 4-SO₂NH₂ OMe I-2 3-NC— —CH₂—O— 4,5-di- H F C 4-Me 3-SO₂NH₂ OMeI-3 3-NC— —CH₂—O— — H F C — 4-SO₂NH₂ I-4 3-NC— —CH₂—O— — H F C —3-SO₂NH₂ I-5 3-NC— —CH₂—O— — H F C — 3-SO₂(4-Me-piperazin-1-yl) I-63-NC— —CH₂—O— — H F C — 4-SO₂(4-Me-piperazin-1-yl) I-7 3-NC— —CH₂—O— — HF C 3-MeO 4-SO₂NH₂ I-8 4-NC— —CH₂—O— — H F C 4-iPr 3-SO₂NH₂ I-9 4-NC——CH₂—O— — H F C 4-(4- 3-SO₂NH₂ Me- piper- azin- 1-yl) I-10 4-NC— —CH₂—O—3-F H F C 4-(4- 3-SO₂NH₂ Me- piper- azin- 1-yl) I-11 4-NC— —CH₂—O— 3-F HF C 4-Me 3-SO₂NH₂ I-12 4-NC— —CH₂—O— 3-F H F C — 3-SO₂NH₂ I-13 4-NC——CH₂—O— — H Br C 4-Me 3-SO₂NH₂ I-14 4-NC— —CH₂—O— — H Br C 4-Me 3-SO₂NH₂I-15 4-NC— —CH₂—O— — H Me₃SiC≡C— C — 3-SO₂NH₂ I-16 4-NC— —CH₂—O— — H F C— 4-SO₂NH₂ I-17 4-NC— —CH₂—O— — H F C — 3-SO₂NH₂ I-18 4-NC— —CH₂—O— — HF C — 4-SO₂(4-Me-piperazin-1-yl) I-19 4-NC— —CH₂—O— — H F C —3-SO₂(4-Me-piperazin-1-yl) I-20 4-NC— —CH₂—O— — H F C 4-Me 3-SO₂NH₂ I-214-NC— —CH₂—O— — H F C 4-Cl 3-SO₂NH₂ I-22 4-NC— —CH₂—O— 3-Me H F C —4-SO₂NH₂ I-23 4-NC— —CH₂—O— 3-Me H F C — 3-SO₂NH₂ I-24 4-NC— —CH₂—O—3-Me H F C 4-Me 3-SO₂NH₂ I-25 4-NC— —CH₂—O— 3,5- H F C — 4-SO₂NH₂ di-MeI-26 4-NC— —CH₂—O— 3,5- H F C — 3-SO₂NH₂ di-Me I-27 4-NC— —CH₂—O— 3,5- HF C 4-Me 3-SO₂NH₂ di-Me I-28 4-NC— —CH₂—O— — H F C 3-Ome 4-SO₂NH₂ I-294-NC— —CH₂—O— — H F C 3-MeO 4-SO₂NH₂ I-30 4-NC— —CH₂—O— — H F C 4-Me3-SO₂NHC(O)Et I-31 4-NC— —CH₂—O— — H F C 4-Me 3-SO₂NHC(O)Et I-32 4-NC——CH₂—O— 3,5- H F C 3-MeO 4-SO₂NH₂ di-Me I-33 4-NC— —CH₂—O— — H F C 4-F3-SO₂NH₂ I-34 4-NC— —CH₂—O— 3-Me H F C 4-F 3-SO₂NH₂ I-35 4-NC— —CH₂—O—3,5- H F C 4-F 3-SO₂NH₂ di-Me I-36 4-NC— —CH₂—O— — H F C 4-Me3-SO₂NHC(O)Me I-37 4-NC— —CH₂—O— — H F C 4-Me 3-SO₂NHC(O)i-Pr I-38 4-NC——CH₂—O— — H F C 4-Me 3-(N(Na)C(O)Me) I-39 4-NC— —CH₂—O— — H F C 4-Me3-(N(Na)C(O)i-Pr) I-40 4-NC— —CH₂—O— 3,5- H F C —4-SO₂(4-Me-piperazin-1-yl) di-Me I-41 4-NC— —CH₂—O— 3-Cl H F C —4-SO₂NH₂ I-42 4-NC— —CH₂—O— 3-Cl H F C — 3-SO₂NH₂ I-43 4-NC— —CH₂—O—3-Cl H F C 4-Me 3-SO₂NH₂ I-44 4-NC— —CH₂—O— 3-F H F C — 4-SO₂NH₂ I-454-NC— —CH₂—O— 3-Ome H F C — 4-SO₂NH₂ I-46 4-NC— —CH₂—O— 3-Ome H F C —3-SO₂NH₂ I-47 4-NC— —CH₂—O— 3-Ome H F C 4-Me 3-SO₂NH₂ I-48 4-NC— —CH₂—O—3-F H F C 4-Me 3-SO₂NHC(O)Et I-49 4-NC— —CH₂—O— 3-F H F C 4-Me3-SO₂N(Na)C(O)Et I-50 4-NC— —CH₂—O— 3- H F C — 3-SO₂NH₂ CH₂OH I-51 4-NC——CH₂—O— 3- H F C 4-Me 3-SO₂NH₂ CH₂OH I-52 4-NC— —CH₂—O— 3-(1- H F C —4-SO₂NH₂ cyano- methyl- (1H)- pyrazol- 3-yl)- I-53 4-NC— —CH₂—O— 3-(1- HF C — 3-SO₂NH₂ cyano- methyl- (1H)- pyrazol- 3-yl)- I-54 4-NC— —CH₂—O—3-(1- H F C 4-Me 3-SO₂NH₂ cyano- methyl- (1H)- pyrazol- 3-yl)- I-554-NC— —CH₂—O— — H F N — 2-SO₂NH₂ I-56 4-NC— —CH₂—O— — H F C 4-Ome3-SO₂NH₂ I-57 4-NC— —CH₂—O— — H Me C — 4-SO₂NH₂ I-58 4-NC— —CH₂—O— — HMe C — 3-SO₂NH₂ I-59 4-NC— —CH₂—O— — H Me C 4-Me 3-SO₂NH₂ I-60 4-NC——CH(Me)O— 3-Me H F C — 4-SO₂NH₂ I-61 4-NC— —CH(Me)O— 3-Me H F C —3-SO₂NH₂ I-62 4-NC— —CH(Me)O— 3-Me H F C 4-Me 3-SO₂NH₂ I-63 4-NC——CH(Me)O— 3,5- H F C — 4-SO₂NH₂ di-Me I-64 4-NC— —CH(Me)O— 3-Me H F C3-MeO 4-SO₂NH₂ I-65 4-NC— —CH(Me)O— — H F C — 3-SO₂NH₂ I-66 4-NC——CH(Me)O— — H F C — 4-SO₂NH₂ I-67 4-NC— —CH(Me)O— — H F C 4-Me 3-SO₂NH₂1-68 4-NC— —CH(Me)O— — H F C 4-F 3-SO₂NH₂ I-69 4-NC— —CH(Me)O— 3-Me H FC 4-F 3-SO₂NH₂ I-70 4-NC— —CH(Me)O— — H F C 3-Ome 4-SO₂NH₂ I-71 4-NC——CH(Me)O— 3,5- H F C — 3-SO₂NH₂ di-Me I-72 4-NC— —CH(Me)O— 3,5- H F C4-Me 3-SO₂NH₂ di-Me I-73 4-NC— —C(Me)₂O— — H F C 4-Me 3-SO₂NH₂ I-744-NC— —C(Me)₂O— — H F C 4-F 3-SO₂NH₂ I-75 4-NC— —C(Me)₂O— — H F C —4-SO₂NH₂ I-76 4-NC— —C(Me)₂O— — H F C — 3-SO₂NH₂ I-77 4-NC— —C(Me)₂O— —H F C 3-MeO 4-SO₂NH₂ I-78 4-NC— —CH₂C(O)NH— — H F C — 3-SO₂NH₂ I-794-NC— —CH₂C(O)NH— — H F C 4-Me 3-SO₂NH₂ I-80 4-NC— —CH₂C(O)NH— 3-Me H FC — 3-SO₂NH₂ I-81 4-NC— —CH₂C(O)NH— 3-Me H F C 4-Me 3-SO₂NH₂ I-82 4-NC——CH₂C(O)NH— 3-Cl H F C — 3-SO₂NH₂ I-83 4-NC— —CH₂C(O)NH— 3-Cl H F C 4-Me3-SO₂NH₂ I-84 4-NC— —CH₂C(O)NH— 3-MeO H F C — 3-SO₂NH₂ I-85 4-NC——CH₂C(O)NH— 3-MeO H F C 4-Me 3-SO₂NH₂ I-86 4-NC— —CH₂C(O)N(CH₃)— — H F C— 3-SO₂NH₂ I-87 4-NC— —CH₂C(O)N(CH₃)— — H F C 4-Me 3-SO₂NH₂ I-883-NH₂C(O)— —CH₂—O— — H F C — 3-SO₂NH₂ I-89 3-NH₂C(O)— —CH₂—O— — H F C —3-SO₂(4-Me-piperazin-1-yl) I-90 3-NH₂C(O)— —CH₂—O— — H F C 4-Me 3-SO₂NH₂I-91 3-NH₂C(O)— —CH₂—O— — H F C — 4-SO₂NH₂ I-92 4-NH₂C(O)— —CH₂—O— 3-MeH F C — 3-SO₂NH₂ I-93 4-NH₂C(O)— —CH₂—O— 3,5- H F C — 3-SO₂NH₂ di-MeI-94 4-NH₂C(O)— —CH₂—O— — H F C 4-Me 3-SO₂NH₂ I-95 4-NH₂C(O)— —CH₂—O—3-Me H F C 4-Me 3-SO₂NH₂ I-96 4-NH₂C(O)— —CH₂—O— 3,5- H F C 4-Me3-SO₂NH₂ di-Me I-97 4-NH₂C(O)— —CH₂—O— 3-Cl H F C — 4-SO₂NH₂ I-984-NH₂C(O)— —CH₂—O— 3-Cl H F C — 3-SO₂NH₂ I-99 4-NH₂C(O)— —CH₂—O— 3-Cl HF C 4-Me 3-SO₂NH₂ I-100 4-NH₂C(O)— —CH₂—O— 3-F H F C — 4-SO₂NH₂ I-1014-NH₂C(O)— —CH₂—O— 3-F H F C — 3-SO₂NH₂ I-102 4-NH₂C(O)— —CH₂—O— 3-F H FC 4-Me 3-SO₂NH₂ I-103 4-NH₂C(O)— —CH₂—O— 3-Ome H F C — 4-SO₂NH₂ I-1044-NH₂C(O)— —CH₂—O— 3-Ome H F C — 3-SO₂NH₂ I-105 4-NH₂C(O)— —CH₂—O— 3-OmeH F C 4-Me 3-SO₂NH₂ I-106 4-NH₂C(O)— —CH₂—O— 3- H F C 4-Me 3-SO₂NH₂CH₂OH I-107 4-NH₂C(O)— —CH₂—O— 3- H F C — 3-SO₂NH₂ CH₂OH I-1084-NH₂C(O)— —CH₂—O— — H Me C — 4-SO₂NH₂ I-109 4-NH₂C(O)— —CH₂—O— — H Me C— 3-SO₂NH₂ I-110 4-NH₂C(O)— —CH₂—O— — H Me C 4-Me 3-SO₂NH₂ I-1114-NH₂C(O)— —CH₂—O— — H F C — 3-SO₂NH₂ I-112 4-NH₂C(O)— —CH₂—O— — H F C —3-SO₂(4-Me-piperazin-1-yl) I-113 4-NH₂C(O)— —CH₂—O— 3-Me H F C —4-SO₂NH₂ I-114 4-NH₂C(O)— —CH₂—O— 3,5- H F C — 4-SO₂NH₂ di-Me I-1154-NH₂C(O)— —CH₂—O— — H F C — 4-SO₂NH₂ I-116 4-NH₂C(O)— —CH(Me)O— — H F C— 4-SO₂NH₂ I-117 4-NH₂C(O)— —CH(Me)O— — H F C — 3-SO₂NH₂ I-1184-NH₂C(O)— —CH(Me)O— — H F C 4-Me 3-SO₂NH₂ I-119 4-NH₂C(O)— —CH(Me)O—3-Me H F C — 4-SO₂NH₂ I-120 4-NH₂C(O)— —CH(Me)O— 3-Me H F C — 3-SO₂NH₂I-121 4-NH₂C(O)— —CH(Me)O— 3-Me H F C 4-Me 3-SO₂NH₂ I-122 4-NH₂C(O)——CH(Me)O— 3,5- H F C — 4-SO₂NH₂ di-Me I-123 4-NH₂C(O)— —CH(Me)O— 3,5- HF C — 3-SO₂NH₂ di-Me I-124 4-NH₂C(O)— —CH(Me)O— 3,4- H F C 4-Me 3-SO₂NH₂di-Me I-125 4-NH₂C(O)— —C(Me)₂O— — H F C — 4-SO₂NH₂ I-126 4-NH₂C(O)——C(Me)₂O— — H F C — 3-SO₂NH₂ I-127 4-NH₂C(O)— —C(Me)₂O— — H F C 4-Me3-SO₂NH₂ I-128 4-Me₂NC(O)— —CH₂—O— — H F C — 4-SO₂NH₂ I-129 4-Me₂NC(O)——CH₂—O— — H F C — 3-SO₂NH₂ I-130 4-Me₂NC(O)— —CH₂—O— — H F C 4-Me3-SO₂NH₂ I-131 4-Me₂NC(O)— —CH₂—O— 3-Cl H F C — 4-SO₂NH₂ I-1324-Me₂NC(O)— —CH₂—O— 3-Cl H F C — 3-SO₂NH₂ I-133 4-Me₂NC(O)— —CH₂—O— 3-ClH F C 4-Me 3-SO₂NH₂ I-134 4-Me₂NC(O)— —CH₂—O— 3-Cl H Me C — 4-SO₂NH₂I-135 4-Me₂NC(O)— —CH₂—O— 3-Cl H Me C — 3-SO₂NH₂ I-136 4-Me₂NC(O)——CH₂—O— 3-Cl H Me C 4-Me 3-SO₂NH₂ I-137 4-Me₂NC(O)— —CH₂—O— 3-F H Me C —4-SO₂NH₂ I-138 4-Me₂NC(O)— —CH₂—O— 3-F H Me C — 3-SO₂NH₂ I-1394-Me₂NC(O)— —CH₂—O— 3-F H Me C 4-Me 3-SO₂NH₂ I-140 4-Me₂NC(O)— —CH₂—O—3-Cl H F C 4-Cl 3-SO₂NH₂ I-141 4-Me₂NC(O)— —CH₂—O— 3-Cl H Me C 4-Cl3-SO₂NH₂ I-142 4-Me₂NC(O)— —CH₂—O— 3-F H Me C 4-Cl 3-SO₂NH₂ I-1434-MeNHC(O)— —CH₂—O— — H F C — 4-SO₂NH₂ I-144 4-MeNHC(O)— —CH₂—O— — H F C— 3-SO₂NH₂ I-145 4-MeNHC(O)— —CH₂—O— — H F C 4-Me 3-SO₂NH₂ I-1464-MeNHC(O)— —CH₂—O— 3-Cl H F C — 4-SO₂NH₂ I-147 4-MeNHC(O)— —CH₂—O— 3-ClH F C — 3-SO₂NH₂ I-148 4-MeNHC(O)— —CH₂—O— 3-Cl H F C 4-Me 3-SO₂NH₂I-149 4-MeNHC(O)— —CH₂—O— 3-Cl H Me C — 4-SO₂NH₂ I-150 4-MeNHC(O)——CH₂—O— 3-Cl H Me C — 3-SO₂NH₂ I-151 4-MeNHC(O)— —CH₂—O— 3-Cl H Me C4-Me 3-SO₂NH₂ I-152 4-MeNHC(O)— —CH₂—O— 3-Cl H F C 4-Cl 3-SO₂NH₂ I-1534-MeNHC(O)— —CH₂—O— 3-Cl H Me C 4-Cl 3-SO₂NH₂ I-154 4-MeNHC(O)— —CH₂—O—3-F H Me C — 4-SO₂NH₂ I-155 4-MeNHC(O)— —CH₂—O— 3-F H Me C — 3-SO₂NH₂I-156 4-MeNHC(O)— —CH₂—O— 3-F H Me C 4-Me 3-SO₂NH₂ I-1574-CH₂═CHCH₂NHC(O)— —CH₂—O— 3-F H F C — 4-SO₂NH₂ I-158 4-CH₂═CHCH₂NHC(O)——CH₂—O— — H F C — 3-SO₂NH₂ I-159 4-CH₂═CHCH₂NHC(O)— —CH₂—O— — H F C 4-Me3-SO₂NH₂ I-160 4-pyridin-2-yl- —CH₂—O— — H F C 4-Me 3-SO₂NH₂ I-1614-pyridin-2-yl- —CH₂—O— — H F C 4-Me 3-SO₂NHMe I-162 4-pyridin-2-yl-—CH₂—O— — H F C — 3-SO₂NH₂ I-163 4-pyridin-2-yl- —CH₂—O— — H F C —4-SO₂NH₂ I-164 4-pyridin-2-yl- —CH₂—O— — H F N — 2-SO₂NH₂ I-1654-pyridin-2-yl- —CH₂—O— — H F C — 4-SO₂NHCH₂CH₂NEt₂ I-1664-pyridin-2-yl- —CH₂—O— — H F C — 3-SO₂NHCH₂CH₂NEt₂ I-1674-pyridin-2-yl- —CH₂—O— 3-Me H F C — 3-SO₂NH₂ I-168 4-pyridin-2-yl-—CH₂—O— 3-Me H F C 4-Me 3-SO₂NH₂ I-169 4-pyridin-2-yl- —CH₂—O— 3-F H F C— 3-SO₂NH₂ I-170 4-pyridin-2-yl- —CH₂—O— 3-Me H F C 4-Me 3-SO₂NHMe I-1714-pyridin-2-yl- —CH₂—O— 3-Cl H F C — 3-SO₂NH₂ I-172 4-pyridin-2-yl-—CH₂—O— 3-F H F C 4-Me 3-SO₂NH₂ I-173 4-pyridin-2-yl- —CH₂—O— 3-F H F C4-Me 3-SO₂NHMe I-174 4-pyridin-2-yl- —CH₂—O— 3-Cl H F C 4-Me 3-SO₂NH₂I-175 4-pyridin-2-yl- —CH₂—O— 3-Cl H F C — 4-SO₂NH₂ I-1764-pyridin-2-yl- —CH₂—O— 3-Me H F C — 4-SO₂NH₂ I-177 4-pyridin-2-yl-—CH₂—O— 3-F H F C — 4-SO₂NH₂ I-178 4-pyridin-2-yl- —CH₂—O— — H Me C 4-Me3-SO₂NH₂ I-179 4-pyridin-2-yl- —CH₂—O— — H Me C — 3-SO₂NH₂ I-1804-pyridin-2-yl- —CH₂—O— — H Me C 4-Me 3-SO₂NHMe I-181 4-pyridin-2-yl-—CH₂—O— — H Me C — 4-SO₂NH₂ I-182 3-pyridin-3-yl- —CH₂—O— — H F C —3-SO₂NH₂ I-183 3-pyridin-3-yl- —CH₂—O— — H F C 4-Me 3-SO₂NH₂ I-1843-pyridin-3-yl- —CH₂—O— — H F C 4-Me 3-SO₂NHMe I-185 3-pyridin-3-yl-—CH₂—O— — H F C — 4-SO₂NH₂ I-186 3-pyridin-3-yl- —CH₂—O— — H F C —4-SO₂NHCH₂CH₂NEt₂ I-187 3-pyridin-3-yl- —CH₂—O— — H F C —3-SO₂NHCH₂CH₂NEt₂ I-188 4-pyridin-3-yl- —CH₂—O— — H F C — 3-SO₂NH₂ I-1894-pyridin-3-yl- —CH₂—O— — H F C 4-Me 3-SO₂NH₂ I-190 4-pyridin-3-yl-—CH₂—O— — H F C 4-Me 3-SO₂NHMe I-191 4-pyridin-3-yl- —CH₂—O— — H F C —4-SO₂NHCH₂CH₂NEt₂ I-192 4-pyridin-3-yl- —CH₂—S— — H F C — 3-SO₂NH₂ I-1934-pyridin-4-yl- —CH₂—O— — H F C — 3-SO₂NH₂ I-194 4-pyridin4-yl- —CH₂—O—— H F C 4-Me 3-SO₂NH₂ I-195 4-pyridin-4-yl- —CH₂—O— 4-Me H F C —3-SO₂NHMe I-196 4-pyridin-4-yl- —CH₂—O— — H F C — 3-SO₂NH₂ I-1974-(3-methyl-(1H)- —CH₂—O— — H F C 4-Me 3-SO₂NH₂ pyrazol-5-yl)- I-1984-(1,3-dimethyl-(1H)- —CH₂—O— — H F C 4-Me 3-SO₂NH₂ pyrazol-5-yl)- I-1994-(1-benzyl-3-methyl- —CH₂—O— — H F C 4-Me 3-SO₂NH₂ (1H)-pyrazol-5-yl)-I-200 4-(2,4-dihydro-3-oxo- —CH₂—O— — H F C 4-F 3-SO₂NH₂1,2,4-triazol-5-yl)- I-201 4-(2,4-dihydro-3-oxo- —CH₂—O— — H F C —3-SO₂NH₂ 1,2,4-triazol-5-yl)- I-202 4-(2,4-dihydro-3-oxo- —CH₂—O— — H FC 4-Me 3-SO₂NH₂ 1,2,4-triazol-5-yl)- I-203 3-morpholin-1-yl- —CH₂CH₂—O—4-Me H F C — 3-SO₂NH₂ I-204 3-morpholin-1-yl- —CH₂CH₂—O— 4-Me H F C 4-Me3-SO₂NH₂ I-205 4-morpholin-1-yl- —CH₂CH₂—O— — H F C — 4-SO₂NH₂ I-2064-morpholin-1-yl- —CH₂CH₂—O— — H F C — 3-SO₂NH₂ I-207 4-morpholin-1-yl-—CH₂CH₂—O— — H F C — 3-SO₂-(morpholin-1-yl) I-208 3-morpholin-1-yl-C(O)——CH₂—O— 4-Me H F C — 3-SO₂NH₂ I-209 3-morpholin-1-yl-C(O)— —CH₂—O— 4-MeH F C — 4-SO₂NH₂ I-210 4-morpholin-1-yl-C(O)— —CH₂—O— — H F C — 4-SO₂NH₂I-211 4-morpholin-1-yl-C(O)— —CH₂—O— — H F C — 3-SO₂NH₂ I-2124-morpholin-1-yl-C(O)— —CH₂—O— — H F C 4-Me 3-SO₂NH₂ I-213 4-CH₃OC(O)——CH₂—O— — H F C 4-Me 3-SO₂NHC(O)Et I-214 3-(5-methylisoxazol-3-yl)-—CH₂—O— — H F C 4-Me 3-SO₂NH₂ I-215 4-(5-methylisoxazol-3-yl)- —CH₂—O— —H F C — 3-SO₂NHCH₂C(O)OMe I-216 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H FC 5-Cl- 3-SO₂NH₂ 4-Me I-217 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C4-F- 3-SO₂NH₂ 5-Me I-218 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C4-Cl- 3-SO₂NH₂ 5-Me I-219 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C4-Me 3-SO₂NH₂ I-220 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C 4-Cl3-SO₂NH₂ I-221 4-(5-methylisoxazol-3-yl)- —CH₂—O— 3-Cl H F C 4-Me3-SO₂NH₂ I-222 4-(5-methylisoxazol-3-yl)- —CH₂—O— 3-F H F C 4-Me3-SO₂NH₂ I-223 4-(5-methylisoxazol-3-yl)- —CH₂—O— 3-F H F C 5-Cl-3-SO₂NH₂ 4-Me I-224 4-(5-methylisoxazol-3-yl)- —CH₂—O— 3-F H F C 4-F-3-SO₂NH₂ 5-Me I-225 4-(5-methylisoxazol-3-yl)- —CH₂—O— — Me F C 4-Me3-SO₂NH₂ I-226 4-(5-methylisoxazol-3-yl)- —CH₂—O— 3-F Me F C 4-Me3-SO₂NH₂ I-227 4-(5-methylisoxazol-3-yl)- —CH₂—O— — CH₂CO₂Me F C 4-Me3-SO₂NH₂ I-228 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C 4-Me3-SO₂NHC(O)Et I-229 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C —3-SO₂NHC(O)i-Pr I-230 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C —3-SO₂NH₂ I-231 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C — 4-SO₂NH₂I-232 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C — 3-SO₂NHC(O)Me I-2334-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C 4-F 3-SO₂NH₂ I-2344-(5-methylisoxazol-3-yl)- —CH₂—O— 3-Me H F C 4-Me 3-SO₂NH₂ I-2354-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C 4-Me 3-SO₂NHMe I-2364-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C — 3-SO₂NHC(O)Et I-2374-(5-methylisoxazol-3-yl)- —CH₂—O— 3-Me H F C 4-F 3-SO₂NH₂ I-2384-(5-methylisoxazol-3-yl)- —CH₂—O— 3-Me H F C — 3-SO₂NH₂ I-2394-(5-methylisoxazol-3-yl)- —CH₂—O— 3-Me H F C 4-Me 3-SO₂NHMe I-2404-(5-methylisoxazol-3-yl)- —CH₂—O— 3-Me H F C — 4-SO₂NH₂ I-2414-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C — 3-SO₂NHCH₂CH₂NEt₂ I-2424-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C — 3-SO₂NHC(O)Et I-2434-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C — 3-SO₂NHC(O)Me I-2444-(5-methylisoxazol-3-yl)- —CH₂—O— 3-Me H F C — 3-SO₂NHCH₂CH₂NEt₂ I-2454-(5-methylisoxazol-3-yl)- —CH₂—O— 3-Me H F C — 4-SO₂NHCH₂CH₂NEt₂ I-2464-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C — 4-SO₂NHCH₂CH₂NEt₂ I-2474-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C —

I-248 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C —

I-249 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C —

I-250 4-(5-methylisoxazol-3-yl)- —CH₂—O— — H F C —

I-251 4-(5-methylisoxazol-3-yl)- —CH₂—O— 3-F H F C 4-(4- 3-SO₂NH₂ Me-piper- azin- 1-yl)- I-252 3-(3-methyl-1,2,4- —CH₂—O— — H F C — 3-SO₂NH₂oxadiazol-5-yl)- I-253 3-(3-methyl-1,2,4- —CH₂—O— — H F C — 4-SO₂NH₂oxadiazol-5-yl)- I-254 3-(3-methyl-1,2,4- —CH₂—O— — H F C 4-Me 3-SO₂NH₂oxadiazol-5-yl)- I-255 3-(3-methyl-1,2,4- —CH₂—O— — H F C 4-Me 3-SO₂NHMeoxadiazol-5-yl)- I-256 3-(3-methyl-1,2,4- —CH₂—O— — H F C —4-SO₂NHCH₂CH₂NEt₂ oxadiazol-5-yl)- I-257 3-(3-methyl-1,2,4-oxadiazol-5-yl)- —CH₂—O— — H F C —

I-258 4-((3-methyl-1,2,4- —CH₂—O— — H F C — 3-SO₂NH₂ oxadiazol-5-yl)-I-259 4-((3-methyl-1,2,4- —CH₂—O— — H F C 4-Me 3-SO₂NH₂ oxadiazol-5-yl)-I-260 4-((3-methyl-1,2,4- —CH₂—O— — H F C 4-Me 3-SO₂NHMeoxadiazol-5-yl)- I-261 4-((3-methyl-1,2,4- —CH₂—O— — H F C —3-SO₂NHCH₂CH₂NEt₂ oxadiazol-5-yl)- I-262 4-((3-methyl-1,2,4- —CH₂—O— — HF C — 3-SO₂NHCH₂CH₂NEt₂ oxadiazol-5-yl)- I-263 4-((3-methyl-1,2,4-—CH₂—O— — H F C — 4-SO₂NHCH₂CH₂NEt₂ oxadiazol-5-yl)- I-2644-((3-methyl-1,2,4- —CH₂—O— — H F C — 3-SO₂NHC(O)Et oxadiazol-5-yl)-I-265 4-((3-methyl-1,2,4- —CH₂—O— — H F C 4-Cl- 3-SO₂NH₂oxadiazol-5-yl)- 3-Me I-266 4-((3-methyl-1,2,4- —CH₂—O— — H F C 4-F3-SO₂NH₂ oxadiazol-5-yl)- I-267 4-((3-methyl-1,2,4- —CH₂—O— — H F C 4-F3-SO₂NH₂ oxadiazol-5-yl)- 1-268 4-((3-methyl-1,2,4- —CH₂—O— — H F C —4-SO₂NH₂ oxadiazol-5-yl)- I-269 4-((3-methyl-1,2,4- —CH₂—O— — Me F C —4-SO₂NH₂ oxadiazol-5-yl)- I-270 4-((3-methyl-1,2,4- —CH₂—O— — Me F C —3-SO₂NH₂ oxadiazol-5-yl)- I-271 4-((3-methyl-1,2,4- —CH₂—O— 6-Ome H F C— 3-SO₂NEt₂ oxadiazol-5-yl)- I-272 4-((3-methyl-1,2,4- —CH₂—O— — H F C —4-SO₂-piperidin-1-yl oxadiazol-5-yl)- I-273 4-((3-methyl-1,2,4- —CH₂—O—— H F C — 3-SO₂N(Na)C(O)Et oxadiazol-5-yl)- I-274 4-((3-methyl-1,2,4-—CH₂—O— — H F C — 3-SO₂(4-Me-piperazin-1-yl) oxadiazol-5-yl)- I-2754-((3-methyl-1,2,4- —CH₂—O— — H F C — 4-SO₂NH₂ oxadiazol-5-yl)- I-2764-((3-methyl-1,2,4- —CH₂—O— — H F C — 3-SO₂NH₂ oxadiazol-5-yl)- I-2774-((3-methyl-1,2,4- —CH₂—O— — H F C — 3-SO₂NH₂ oxadiazol-5-yl)- I-2784-((3-methyl-1,2,4- —CH₂—O— — H F C 4-F 3-SO₂NH₂ oxadiazol-5-yl)- I-2794-((3-methyl-1,2,4- —CH₂—O— — H F C 4-Me 3-SO₂NH₂ oxadiazol-5-yl)- I-2804-(2-Me-thiazol-4-yl)- —CH₂—O— — H F C 4-Me 3-SO₂NH₂ I-2814-(2-Me-thiazol-4-yl)- —CH₂—O— — H F C — 3-SO₂NH₂ I-2824-(2-Me-thiazol-4-yl)- —CH₂—O— — H F C 4-Me 3-SO₂NHMe I-2834-(2-Me-thiazol-4-yl)- —CH₂—O— — H F C — 3-SO₂NHCH₂CH₂NEt₂ I-2844-(2-Me-thiazol-4-yl)- —CH₂—O— — H F C — 4-SO₂NHCH₂CH₂NEt₂ I-2854-(2-Me-thiazol-4-yl)- —CH₂—O— — H F C — 4-SO₂NH₂

TABLE II

# R¹— —Y— (R²)_(p) R X Z (R³)_(q) SO₂NR⁴R⁵ II-1 3-(N-Me-piperidin-3-yl)- —O— — H F C 4-Me 3-SO₂NH₂ II-2 3-(N-Me-piperidin-4-yl)- —O— — H F C 4-Me 3-SO₂NH₂ II-3 4-(N-Me-piperidin-3-yl)- —O— 3-Cl H F C 4-Me 3-SO₂NH₂ II-4 4-(N-Me-piperidin-3-yl)- —O— — H F C 4-Me 3-SO₂NH₂ II-5 4-(N-Me-piperidin-4-yl)- —O— 3-Me H F C 4-Me 3-SO₂NH₂ II-6 4-(N-Me-piperidin-4-yl)- —O— 3-CF₃ H F C 4-Me 3-SO₂NH₂ II-7 4-(N-Me-piperidin-4-yl)- —O— — H F C 4-Me 3-SO₂NH₂ II-8 4-(N-Me-piperidin-4-yl)- —O— 3-Cl H F C 4-Me 3-SO₂NH₂ II-9 4-(N-Me-pyrrolidin-3-yl)- —O— — H F C — 3-SO₂NH₂ II-104-(N-Me-pyrrolidin-3-yl)- —O— — H F C 4-Me 3-SO₂NH₂ II-114-(pyridin-3-yl)- —O— — H F C — 3-SO₂NH₂ II-12 4-(pyridin-3-yl)- —O— — HF C 4-Me 3-SO₂NH₂ II-13 4-(pyridin-3-yl)- —O— — H F C 4-Me 3-SO₂NHMeII-14 4-(pyridin-3-yl)- —O— — H F C — 4-SO₂NHMe II-15 4-(pyridin-3-yl)-—O— — H F C 3-SO₂NH₂ 4-SO₂NH₂ II-16 4-(pyridin-4-yl)- —O— — H F C 4-Me3-SO₂NH₂ II-17 4-(pyridin-4-yl)- —O— — H F C — 3-SO₂NH₂ II-184-(pyridin-4-yl)- —O— — H F C 4-Me 3-SO₂NHMe II-194-(1-methyl-(1H)-pyrazol-3-yl)- —NHC(O)— — H F C 4-Me 3-SO₂NH₂ II-204-(2-ethyl-(2H)-pyrazol-3-yl)- —NHC(O)— — H F C 4-Me 3-SO₂NH₂ II-214-(2-methyl-(2H)-pyrazol-3-yl)- —NHC(O)— — H F C 4-Me 3-SO₂NH₂ II-224-(pyrazol-(2H)-3-yl)- —NHC(O)— — H F C 4-Me 3-SO₂NH₂

TABLE III

# R¹— -alk- (R²)_(p) R X Z (R³)_(q) SO₂NR⁴R⁵ III-1  4-NC— —CH₂— — H F C4-Me 3-SO₂NHMe III-2  4-NC— —CH₂— — H F C — 4-SO₂NHCH₂CH₂NEt₂ III-3 4-NC— —CH₂— — H F C — 4-SO₂NH₂ III-4  4-NC— —CH₂— — H F C — 3-SO₂NH₂III-5  4-NC— —CH₂— — H F C — 3-SO₂(4-Me-piperazin-1-yl) III-6  4-NC——CH₂— — H F C — 4-SO₂(4-Me-piperazin-1-yl) III-7  4-NC— —CH₂— — H F C4-Me 3-SO₂NH₂ III-8  4-NC— —CH₂— — H F C 4-Cl 3-SO₂NH₂ III-9  4-NC——CH₂— — H F C 3-Ome 4-SO₂NH₂ III-10  4-NC— —CH₂— — H F C 4-F 3-SO₂NH₂III-11  4-NC— —CH₂CH₂— — H Me C 4-Me 3-SO₂NH₂ III-12  4-NC— —CH₂CH₂— — HMe C 4-Cl 3-SO₂NH₂ III-13  4-NC— —CH₂CH₂— — H F C 4-Cl 3-SO₂NH₂ III-14 4-NC— —CH₂CH₂— — H F C — 3-SO₂NH₂ III-15  4-NC— —CH₂CH₂— — H F C 4-Me3-SO₂NH₂ III-16  4-NC— —CH₂CH₂— — H F C 4-F 3-SO₂NH₂ III-17  4-NC——CH₂CH₂— 3-F H F C 4-Me 3-SO₂NH₂ III-18  4-NC— —CH₂CH₂— 3-F H F C —3-SO₂NH₂ III-19  4-NC— —CH₂CH₂— 3-Me H F C 4-Me 3-SO₂NH₂ III-20  4-NC——CH₂CH₂— 3-Me H F C — 3-SO₂NH₂ III-21  4-NC— —CH₂CH₂— 3-Cl H F C 4-Me3-SO₂NH₂ III-22  4-NC— —CH₂CH₂— 3-Cl H F C — 3-SO₂NH₂ III-23  3-NC——CH₂CH₂— 6-Me H F C 4-Me 3-SO₂NH₂ III-24  3-NC— —CH₂CH₂— 6-Me H F C —3-SO₂NH₂ III-25  4-NC— —CH₂CH₂— 3-MeO H F C 4-Me 3-SO₂NH₂ III-26  4-NC——CH₂CH₂— 3-MeO H F C — 3-SO₂NH₂ III-27  4-NC— —CH₂CH₂— — H Me C —4-SO₂NH₂ III-28  4-NC— —CH₂CH₂— 3-Cl H F C 4-Me 3-SO₂NHC(O)Et III-29 4-NC— —CH₂CH₂— 3-Cl H F C 4-Me 3-SO₂NHC(O)Et III-30  4-NC— —CH₂CH₂—4-CF₃ H F C 4-Me 3-SO₂NH₂ III-31  4-NC— —CH₂CH₂— 4-CF₃ H F C — 3-SO₂NH₂III-32  4-NH₂C(O)NH— —CH₂— — H F C — 4-SO₂NH₂ III-33  4-NH₂C(O)NH— —CH₂—— H F C — 3-SO₂NH₂ III-34  4-NH₂C(O)NH— —CH₂— — H F C 4-Me 3-SO₂NH₂III-35  4-CH₃CH₂C(O)NH— —CH₂— — H F C — 4-SO₂NH₂ III-36  4-CH₃CH₂C(O)NH——CH₂— — H F C — 3-SO₂NH₂ III-37  4-CH₃CH₂C(O)NH— —CH₂— — H F C 4-Me3-SO₂NH₂ III-38  3-cyclopropyl-C(O)NH— —CH₂— — H F C — 4-SO₂NH₂ III-39 3-cyclopropyl-C(O)NH— —CH₂— — H F C — 3-SO₂NH₂ III-40 3-cyclopropyl-C(O)NH— —CH₂— — H F C 4-Me 3-SO₂NH₂ III-41 4-cyclopropyl-C(O)NH— —CH₂— — H F C — 4-SO₂NH₂ III-42 4-cyclopropyl-C(O)NH— —CH₂— — H F C — 3-SO₂NH₂ III-43 4-cyclopropyl-C(O)NH— —CH₂— — H F C 4-Me 3-SO₂NH₂ III-44 4-CH₂═CHC(O)NH— —CH₂— — H F C — 4-SO₂NH₂ III-45  4-CH₂═CHC(O)NH— —CH₂— —H F C — 3-SO₂NH₂ III-46  4-CH₂═CHC(O)NH— —CH₂— — H F C 4-Me 3-SO₂NH₂III-47  4-H₂NC(O)— —CH₂CH₂— — H F C 4-Me 3-SO₂NH₂ III-48  4-H₂NC(O)——CH₂CH₂— — H F C — 3-SO₂NH₂ III-49  4-H₂NC(O)— —CH₂CH₂— — H F C —4-SO₂NH₂ III-50  4-(1-methyl-(2H)-pyrazol-3-yl)-NHC(O)— —CH₂— — H F C —3-SO₂NH₂ III-51  4-(2-ethyl-(2H)-pyrazol-3)-NHC(O)— —CH₂— — H F C —3-SO₂NH₂ III-52  4-(2-ethyl-(2H)-pyrazol-3)-NHC(O)— —CH₂— — H F C 4-Me3-SO₂NH₂ III-53  4-NH₂C(O)O— —CH₂CH₂— — H F C 4-Me 3-SO₂NH₂ III-54 4-NH₂C(O)O— —CH₂CH₂— — H F C — 3-SO₂NH₂ III-55  4-NH₂C(O)O— —CH₂CH₂— — HF C 4-Cl 3-SO₂NH₂ III-56  4-Me₂NC(O)O— —CH₂CH₂— — H F C 4-Me 3-SO₂NH₂III-57  4-Me₂NC(O)O— —CH₂CH₂— — H F C — 3-SO₂NH₂ III-58  4-Me₂NC(O)O——CH₂CH₂— — H F C 4-Cl 3-SO₂NH₂ III-59  4-Me₂NC(O)O— —CH₂CH₂— — H F C4-Me 3-SO₂NH₂ III-60  4-Me₂NC(O)O— —CH₂CH₂— — H F C — 3-SO₂NH₂ III-61 4-Me₂NC(O)O— —CH₂CH₂— — H F C 4-Cl 3-SO₂NH₂ III-62  phenyl —CH₂— — H F C— 3-SO₂NH₂ III-63  phenyl —CH₂— — H F C 4-Me 3-SO₂NH₂ III-64  phenyl—CH₂— — H F C 4-Cl 3-SO₂NH₂ III-65  phenyl —CH₂— — H F C 4-MeO, 5-Me3-SO₂NH₂ III-66  4-pyridin-4-yl- —CH₂— — H F C 4-Ome 3-SO₂NH₂ III-67 4-pyridin-4-yl- —CH₂— — H F C — 3-SO₂NHCH₂CH₂NEt₂ III-68 4-pyridin-4-yl- —CH₂— — H F C — 3-SO₂NHC(O)Et III-69  4-pyridin-4-yl-—CH₂— — H F C — 3-SO₂N(Na)C(O)Et III-70  4-pyridin-4-yl- —CH₂— — H F C —3-SO₂NH₂ III-71  4-pyridin-4-yl- —CH₂— — H F C — 4-SO₂NH₂ III-72 4-pyridin-4-yl- —CH₂— — H F C — 4-SO₂NHCH₂CH₂NEt₂ III-73 4-pyridin-4-yl- —CH₂— — H F C — 3-SO₂NH₂ III-74  4-pyridin-4-yl- —CH₂— —H F C 4-Me 3-SO₂NH₂ III-75  4-pyridin-4-yl- —CH₂— — H F C 4-Me 3-SO₂NHMeIII-76  4-pyridin-4-yl- —CH₂CH₂— — H F C — 3-SO₂NH₂ III-77 4-pyridin-4-yl- —CH₂CH₂— — H F C 4-Me 3-SO₂NH₂ III-78  4-pyridin-4-yl-—CH₂CH₂— — H F C 4-Me 3-SO₂NHMe III-79  4-pyridin-4-yl- —CH₂CH₂— — H F C— 4-SO₂NH₂ III-80  4-(N-hydroxy-pyridin-4-yl)- —CH₂— — H F C —3-SO₂NHC(O)Et III-81  4-imidazol-1-yl- —CH₂— — H F C — 3-SO₂NH₂ III-82 4-imidazol-1-yl- —CH₂— — H F C 4-Me 3-SO₂NH₂ III-83  4-imidazol-1-yl-—CH₂— — H F C 4-Me 3-SO₂NHMe III-84  4-imidazol-1-yl- —CH₂— — H F C —4-SO₂NHCH₂CH₂N(Et)₂ III-85  4-imidazol-1-yl- —CH₂— — H F C 4-Me3-SO₂NHMe III-86  4-imidazol-1-yl- —CH₂— — H F C 4-Me 3-SO₂NHMe III-87 4-imidazol-1-yl- —CH₂CH₂— — H F C — 3-SO₂NH₂ III-88  4-imidazol-1-yl-—CH₂CH₂— — H F C 4-Me 3-SO₂NH₂ III-89  4-imidazol-1-yl- —CH₂CH₂— — H F C4-Me 3-SO₂NHMe III-90  4-imidazol-1-yl- —CH₂CH₂— — H F C — 4-SO₂NH₂III-91  4-(2-methyl-imidazol-1-yl)- —CH₂— — H F C 4-Me 3-SO₂NH₂ III-92 4-(2-methyl-imidazol-1-yl)- —CH₂— — H F C — 4-SO₂NH₂ III-93 4-(2-methyl-imidazol-1-yl)- —CH₂— — H F C 4-Me 3-SO₂NHMe III-94 4-(2-methyl-imidazol-1-yl)- —CH₂— — H F C — 3-SO₂NH₂ III-95 4-(1H-1,2,3-triazol-1-yl)- —CH₂— — H F C 4-Me 3-SO₂NH₂ III-96 4-(1H-1,2,3-triazol-1-yl)- —CH₂— — H F C — 4-SO₂NH₂ III-97 4-(1H-1,2,3-triazol-1-yl)- —CH₂— — H F C — 3-SO₂NH₂ III-98 4-(1H-1,2,3-triazol-1-yl)- —CH₂— — H F C 4-Me 3-SO₂NHMe III-99 4-(1H-1,2,4-triazol-1-yl)- —CH₂— — H F C — 4-SO₂NH₂ III-1004-(1H-1,2,4-triazol-1-yl)- —CH₂— — H F C — 3-SO₂NH₂ III-1014-(1H-1,2,4-triazol-1-yl)- —CH₂— — H F C 4-Me 3-SO₂NH₂ III-1024-(1H-1,2,4-triazol-1-yl)- —CH₂— — H F C 4-Me 3-SO₂NHMe III-1034-morpholin-1-yl- —CH₂— — H F C — 3-SO₂NH₂ III-104 4-morpholin-1-yl-—CH₂— — H F C 4-Me 3-SO₂NH₂ III-105 4-morpholin-1-yl- —CH₂— — H F C4-Ome 3-SO₂NH₂ III-106 4-(3-methyl-1,2,4-oxadiazol-5-yl)- —CH₂CH₂— — H FC — 3-SO₂NH₂ III-107 4-(thiomorpholin-1-yl)- —CH₂— — H F C — 3-SO₂NH₂III-108 4-(thiomorpholin-1-yl)- —CH₂— — H F C 4-Me 3-SO₂NH₂ III-1094-(thiomorpholin-1-yl)-- —CH₂— — H F C 4-Ome 3-SO₂NH₂ III-1104-(S,S-dioxo-thiomorpholin-1-yl)- —CH₂— — H F C — 3-SO₂NH₂ III-1114-(S,S-dioxo-thiomorpholin-1-yl)- —CH₂— — H F C 4-Me 3-SO₂NH₂ III-1124-(S,S-dioxo-thiomorpholin-1-yl)- —CH₂— — H F C 4-Ome 3-SO₂NH₂ III-1133-H₂NC(O)NH— —CH₂— — H F C — 4-SO₂NH₂ III-114 3-H₂NC(O)NH— —CH₂— — H F C— 3-SO₂NH₂ III-115 3-H₂NC(O)NH— —CH₂— — H F C 4-Me 3-SO₂NH₂ III-1163-CH₃CH₂NHC(O)NH— —CH₂— — H F C — 4-SO₂NH₂ III-117 3-CH₃CH₂NHC(O)NH——CH₂— — H F C — 3-SO₂NH₂ III-118 3-CH₃CH₂NHC(O)NH— —CH₂— — H F C 4-Me3-SO₂NH₂ III-119 4-CH₃CH₂NHC(O)NH— —CH₂— — H F C — 4-SO₂NH₂ III-1204-CH₃CH₂NHC(O)NH— —CH₂— — H F C — 3-SO₂NH₂ III-121 4-CH₃CH₂NHC(O)NH——CH₂— — H F C 4-Me 3-SO₂NH₂ III-122 4-CH₃CH₂NHC(O)NH— —CH₂CH₂— — H F C —4-SO₂NH₂ III-123 4-CH₃CH₂NHC(O)NH— —CH₂CH₂— — H F C — 3-SO₂NH₂ III-1244-CH₃CH₂NHC(O)NH— —CH₂CH₂— — H F C 4-Me 3-SO₂NH₂ III-1254-H₂NC(O)N(CH₃CH₂CH₂)— —CH₂— — H F C — 4-SO₂NH₂ III-1264-H₂NC(O)N(CH₃CH₂CH₂)— —CH₂— — H F C — 3-SO₂NH₂ III-1274-H₂NC(O)N(CH₃CH₂CH₂)— —CH₂— — H F C 4-Me 3-SO₂NH₂ III-1284-pyrindin-4-yl —CH₂— — H F C — 3-SO₂NH₂ III-129 4-pyrindin-4-yl —CH₂— —H F C — 3-SO₂NH₂

TABLE IV

# R¹— (R²)_(p) R X Z (R³)_(q) SO₂NR⁴R⁵ IV-1  3-(oxazol-5-yl) — H F C —3-SO₂NH₂ IV-2  3-(oxazol-5-yl) — H F C 4-Me 3-SO₂NH₂ IV-3 3-(oxazol-5-yl) — H F C — 4-SO₂NH₂ IV-4  3-(oxazol-5-yl) — H F C 4-Me3-SO₂NHMe IV-5  4-(oxazol-5-yl) — H F C — 3-SO₂NH₂ IV-6  4-(oxazol-5-yl)— H F C 4-Me 3-SO₂NH₂ IV-7  4-(oxazol-5-yl) — H F C 4-Me 3-SO₂NHMe IV-8 4-(oxazol-5-yl) — H F C — 4-SO₂NH₂ IV-9  4-(N,N- — H F C — 3-SO₂NH₂dimethylsulfamoyl)- IV-10 4-(N,N- — H F C 4-Me 3-SO₂NH₂dimethylsulfamoyl)- IV-11 4-(N-methylsulfamoyl)- — H F C — 3-SO₂NH₂IV-12 4-(N-methylsulfamoyl)- — H F C 4-Me 3-SO₂NH₂

TABLE V

#

R¹-alk-Y (R²)_(p) (R³)_(q) NR⁴R⁵ V-1  pyridin-3-yl6-((5-methylisoxazol-3-yl)-CH₂O)— — 4-Me 3-SO₂NH₂ V-2 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 4-((pyridin-2-yl)-CH₂—) 3-oxo4-Me 3-SO₂NH₂ V-3  3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl4-(pyridin-2-yl)-CH₂— 3-oxo — 4-SO₂NH₂ V-4 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 4-methoxybenzyl 2-Me, 3-oxo —4-SO₂NH₂ V-5  3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 4-methoxybenzyl2-Me, 3-oxo — 3-SO₂NH₂ V-6  3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl4-NC—CH₂— 3-oxo — 4-SO₂NH₂ V-7  3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl4-NC—CH₂— 3-oxo — 3-SO₂NH₂ V-8  3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl4-NC—CH₂— 3-oxo 4-Me 3-SO₂NH₂ V-9 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 4-methoxybenzyl 2-Me, 3-oxo4-Me 3-SO₂NH₂ V-10 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl4-methoxybenzyl 2-Me, 3-oxo — 4-SO₂NH₂ V-113,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 4-NC—CH₂— 3-oxo — 4-SO₂NH₂ V-123,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 4-NC—CH₂— 3-oxo — 3-SO₂NH₂ V-133,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 4-NC—CH₂— 3-oxo 4-Me 3-SO₂NH₂V-14 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl 4-NC—CH₂— 2,2,-diMe,3-oxo 4-Me 3-SO₂NH₂ V-15 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl4-NC—CH₂— 2,2,-diMe, 3-oxo 4-Cl 3-SO₂NH₂ V-16 benzo[b]thiophen-5-yl2-NC—(CH₂)₂— — 4-Me 3-SO₂NH₂ V-17 4H-pyrido[1,4]oxazin-6-yl —2,2-diMe-3-oxo — 3-SO₂NH₂ V-18 4H-pyrido[1,4]oxazin-7-yl —2,2-diMe-3-oxo 4-Me 3-SO₂NH₂ V-19 piperidin-3-yl 1 -NCCH₂C(O)— 4-Me 4-Me3-SO₂NH₂

TABLE VI

# (R²)_(p) R X Z (R³)_(q) NR⁴R⁵ VI-1  3-OH H F C 3-OMe 4-SO₂NHMe VI-2 3-Cl-4-OMe H F C 4-Cl 3-SO₂NH₂ VI-3  3,4-di-Cl H F C 4-Cl 3-SO₂NH₂ VI-4 3-Cl-4-OMe H F C 4-Me 3-SO₂NH₂ VI-5  4-Cl-3-OMe H F C 4-Me 3-SO₂NH₂VI-6  3,4-di-Cl H F C 4-Me 3-SO₂NH₂ VI-7  3-Cl-4-OMe H F C —3-SO₂NHCH₂COOMe VI-8  3,4-di-Cl H F C — 3-SO₂NHCH₂COOMe VI-9  3-Cl-4-OMeH F C — 3-SO₂NH(1-Me-piperidin-4-yl) VI-10  3,4-di-Cl H F C —3-SO₂NH(1-Me-piperidin-4-yl) VI-11  4-Cl-3-OMe H F C 4-Cl 3-SO₂NH₂VI-12  3-Cl-4-OMe H F C 4-Cl 3-SO₂NHC(O)Me VI-13  3-Cl-4-OMe H F C4-Me-5-Cl 3-SO₂NH₂ VI-14  3-Cl-4-OCF₃ H F C 4-Me-5-Cl 3-SO₂NH₂ VI-15 3-Cl-4-OMe H F C 4-F-5-Me 3-SO₂NH₂ VI-16  3-Cl-4-OCF₃ H F C 4-F-5-Me3-SO₂NH₂ VI-17  3-Cl-4-OMe H F C 4-Cl-5-Me 3-SO₂NH₂ VI-18  3-Cl-4-OCF₃ HF C 4-Cl-5-Me 3-SO₂NH₂ VI-19  3-Cl-4-OMe Me F C 4-Me 3-SO₂NH₂ VI-20 3-Cl-4-OMe Me F C 4-F-5-Me 3-SO₂NH₂ VI-21  3-Cl-4-OMe Me F C 4-Cl-5-Me3-SO₂NH₂ VI-22  3-Cl-4-OMe pr F C 4-Me 3-SO₂NH₂ VI-23  3-Cl-4-OMe pr F C4-F-5-Me 3-SO₂NH₂ VI-24  3-Cl-4-OMe CH₂C(O)OEt C(O)OEt C — 3-SO₂NH₂VI-25  3-Cl-4-OMe CH₂C(O)OEt C(O)OEt C 4-Me 3-SO₂NH₂ VI-26  3-Cl-4-OMe HBr C — 3-SO₂NH₂ VI-27  3-Cl-4-OMe H Br C 4-Me 3-SO₂NH₂ VI-28  3-Cl-4-OMeH Me₃SiC≡C— C — 3-SO₂NH₂ VI-29  3-Cl-4-OMe H F C 4-OMe 3-SO₂NH₂ VI-30 3-Cl-4-OMe H F C 3-Me-4-OMe 3-SO₂NH₂ VI-31  3-Cl-4-OMe H F N — 2-SO₂NH₂VI-32  4-OCF₃ H F C 4-Me 3-SO₂NH₂ VI-33  4-OCF₃ H F C — 3-SO₂NH₂ VI-34 4-OCF₃ H F C 4-MeO, 5-Me 3-SO₂NH₂ VI-35  4-t-butyl H F C — 3-SO₂NH₂VI-36  4-t-butyl H F C 4-Me 3-SO₂NH₂ VI-37  4-t-butyl H F C 4-MeO, 5-Me3-SO₂NH₂ VI-38  3-CF₃-4-Cl H F C 4-MeO, 5-Me 3-SO₂NH₂ VI-39  3-CF₃-4-ClH F C 4-Me 3-SO₂NH₂ VI-40  3-CF₃-4-Cl H F C — 3-SO₂NH₂ VI-41  4-CF₃ H FC 4-Cl 3-SO₂NH₂ VI-42  4-OCF₃ H F C 4-Cl 3-SO₂NH₂ VI-43  4-t-butyl H F C4-Cl 3-SO₂NH₂ VI-44  3-Cl-4-CF₃ H F C 4-Cl 3-SO₂NH₂ VI-45  3-Cl-4-MeO HF C 4-isopropyl 3-SO₂NH₂ VI-46  4-OCF₃ H F C 4-Me 3-SO₂NH₂ VI-47  4-OCF₃H F C — 3-SO₂NH₂ VI-48  4-OCF₃ H F C 4-Cl 3-SO₂NH₂ VI-49  3-CH₂OC(O)NHMeH F C 4-Me 3-SO₂NH₂ VI-50  4-CF₃ H F C 4-Me 3-SO₂NH₂ VI-51  4-CF₃ H F C— 3-SO₂NH₂ VI-52  4-CH₂OH H F C 4-Me 3-SO₂NH₂ VI-53  4-HC≡C—CH₂O— H F C4-Me 3-SO₂NH₂ VI-54  4-(CH₂═CH)— H F C 4-Me 3-SO₂NH₂ VI-55  4-HC≡C—CH₂O—H F C 4-Cl 3-SO₂NH₂ VI-56  4-HC≡C—CH₂O— H F C 4-Me 3-SO₂NHC(O)Et VI-57 3-HC≡C—CH₂O— H F C 4-Me 3-SO₂NH₂ VI-58  4-(HC≡C—CH₂O)-3-Me H F C 4-Me3-SO₂NH₂ VI-59  4-(HC≡C—CH₂O)-3-Cl H F C 4-Me 3-SO₂NH₂ VI-60 4-(HC≡C—CH₂O)-3-F H F C 4-Me 3-SO₂NH₂ VI-61  4-MeC≡C—CH₂O— H F C 4-Me3-SO₂NH₂ VI-62  4-prop-2-ynyloxy H F C 4-Me 3-SO₂NHC(O)Et VI-63 4-prop-2-ynyloxy H F C 4-isopropyl 3-SO₂NH₂ VI-64  4-diMe-carbamate-Et HF C — 3-SO₂NHC(O)Et VI-65  4-prop-2-ynylamine H F C 4-Me 3-SO₂NH₂ VI-66 4-diMe-carbamate-Et H F C — 3-SO₂NHC(O)Et VI-67  4-(di-prop-2-ynyl)amineH F C 4-Me 3-SO₂NH₂ VI-68  4-prop-2-ynyloxy H F C 4-Me 3-SO₂NHMe VI-69 4-prop-2-ynyloxy H F C 4-Me 3-SO₂NH(1-Me-piperidin-4-yl) VI-70 4-prop-2-ynyloxy H F C 4-(1-Me-piperizin-4-yl) 3-SO₂NH₂ VI-71 4-ethylurea H F C 4-Me 3-SO₂NH₂ VI-72  4-ethylurea H F C — 3-SO₂NH₂VI-73  4-HC≡C—CH₂OC(O)NHCH₂ H F C 4-Me 3-SO₂NH₂ VI-74 4-HC≡C—CH₂OC(O)NHCH₂ H F C — 3-SO₂NH₂ VI-75  4-HC≡C—CH₂NHSO₂— H F C —3-SO₂NH₂ VI-76  4-HC≡C—CH₂NHSO₂— H F C 4-Me 3-SO₂NH₂ VI-77 4-HC≡C—CH₂NHSO₂— H F C — 4-SO₂NH₂ VI-78  4-HC≡C—CH₂O H F C —3-SO₂NHCH₂C≡CH VI-79  3-HC≡C—CH₂NHSO₂— H F C 4-Me 3-SO₂NH₂ VI-80 3-HC≡C—CH₂NHSO₂— H F C — 4-SO₂NH₂ VI-81  3-HC≡C—CH₂NHSO₂— H F C —3-SO₂NH₂ VI-82  4-(F(CH₂)₃)— H F C — 4-SO₂NH₂ VI-83  4-(F(CH₂)₃)— H F C— 3-SO₂NH₂ VI-84  4-(F(CH₂)₃)— H F C 4-Me 3-SO₂NH₂ VI-85  4-(OH(CH₂)₃)—H F C — 4-SO₂NH₂ VI-86  4-(OH(CH₂)₃)— H F C — 3-SO₂NH₂ VI-87 4-(OH(CH₂)₃)— H F C 4-Me 3-SO₂NH₂ VI-88  4-(OH(CH₂)₄)— H F C — 4-SO₂NH₂VI-89  4-(OH(CH₂)₄)— H F C — 3-SO₂NH₂ VI-90  4-(OH(CH₂)₄)— H F C 4-Me3-SO₂NH₂ VI-91  4-(F(CH₂)₄)— H F C — 4-SO₂NH₂ VI-92  4-(F(CH₂)₄)— H F C— 3-SO₂NH₂ VI-93  4-(F(CH₂)₄)— H F C 4-Me 3-SO₂NH₂ VI-94  4-HSCH₂C(O)— HF C — 4-SO₂NH₂ VI-95  4-HSCH₂C(O)— H F C 4-Me 3-SO₂NH₂ VI-96  3-CN-4-MeH F C — 3-SO₂NHBu VI-97  3-Cl-4-F H F C — 3-SO₂NHBu VI-98  3-CN-4-F H FC — 3-SO₂NH₂ VI-99  3-CN-4-Me H F C — 3-SO₂NH₂ VI-100 4-OH H F C 4-F3-SO₂NH₂ VI-101 4-OH H F C — 3-SO₂NH₂ VI-102 4-OH H F C 4-Me 3-SO₂NH₂VI-103 3-Me-4-CH₂CH₂CN H F C 4-Me 3-SO₂NHC(O)Et VI-104 3-Me-4-CH₂CH₂CN HF C 4-Me 3-SO₂N(Na)C(O)Et VI-105 3,4-di-Cl Me F C 6-Ome 3-SO₂NEt₂ VI-1063-Cl-4-Ome H F C — 4-SO₂NH₂ VI-107 3-Cl-4-Ome H F C — 3-SO₂NH₂ VI-1083-Cl-4-Ome H F C 6-Ome 3-SO₂NEt₂ VI-109 3,4-di-Cl H F C — 4-SO₂NH₂VI-110 3,4-di-Cl H F C — 3-SO₂NH₂ VI-111 4-OCH₂CH₂Ome H F C 4-Cl3-SO₂NH₂ VI-112 4-OCH₂CH₂Ome H F C 4-Me 3-SO₂NH₂ VI-113 3-H₂NSO₂— H F C— 3-SO₂NH₂ VI-114 3-H₂NSO₂-4-Me H F C 4-Me 3-SO₂NH₂ VI-115 3-H₂NSO₂-4-ClH F C 4-Cl 3-SO₂NH₂ VI-116 3-Cl-4-MeO H F C 4-(4-Me-piperazin-1-yl)3-SO₂NH₂

TABLE VII

#

(R²)_(p) R X (R³)_(q) NR⁴R⁵ VII-1  (2S,4R)-pyrrolidin-4-yl1-(CNCH₂C(O))-2-C(O)OME H F 4-Me 3-SO₂NH₂ VII-2  (2S,4S)-pyrrolidin-4-yl1-(CNCH₂C(O))-2-C(O)OME H F 4-Me 3-SO₂NH₂ VII-3  piperidin-3-yl1-benzyl-4-Me H F 4-Me 3-SO₂NH₂ VII-4  piperidin-3-yl 4-Me H F 4-Me3-SO₂NH₂ VII-5  piperidin-3-yl 1-C(O)CH₂CN-4-Me H F 4-Me 3-SO₂NH₂ VII-6 pyridin-5-yl 2-OMe H F — 3-SO₂NH₂ VII-7  pyridin-6-yl 2-NH₂-3-OMe H F —3-SO₂NH₂ VII-8  pyridin-6-yl 2-NH₂-3-OMe H F 4-Cl 3-SO₂NH₂ VII-9 pyridin-6-yl 2-NH₂-3-OMe H F 4-Me 3-SO₂NH₂ VII-10 pyridin-6-yl2-NH₂-3-OMe H F 4-Cl 3-SO₂NHCH₂COOEt VII-11

H F — 3-SO₂NH₂ VII-12

H F — 4-SO₂NH₂ VII-13 1,2,3,4-tetrahydroisoquinolin-6-yl2-(ethylsulfonyl) H F — 4-SO₂NH₂ VII-141,2,3,4-tetrahydroisoquinolin-6-yl 2-(ethylsulfonyl) H F — 3-SO₂NH₂VII-15 1,2,3,4-tetrahydroisoquinolin-6-yl 2-(ethylsulfonyl) H F 4-Me3-SO₂NH₂ VII-16 1,2,3,4-tetrahydroisoquinolin-7-yl — H F 4-Me 3-SO₂NH₂VII-17 1,2,3,4-tetrahydroisoquinolin-7-yl 2-C(O)NHMe H F 4-Me 3-SO₂NH₂VII-18 1,2,3,4-tetrahydroisoquinolin-7-yl 2-C(O)NMe₂ H F 4-Me 3-SO₂NH₂VII-19 1,2,3,4-tetrahydroquinolin-6-yl 1-C(O)NHMe H F 4-Me 3-SO₂NH₂VII-20 1,2,3,4-tetrahydroquinolin-6-yl 1-C(O)NHMe H F — 3-SO₂NH₂ VII-211,2,3,4-tetrahydroquinolin-6-yl 2-oxo H F 4-Me 3-SO₂NH₂ VII-221H-indazol-5-yl 1-(3-methoxypropyl) H F — 3-SO₂NH₂ VII-231H-indazol-5-yl 1-(2-methoxyethyl) H F — 3-SO₂NH₂ VII-242,3-dihydrobenzodioxin6-yl — H F — 4-SO₂N-(1-pyrrolidinyl) VII-252,3-dihydrobenzodioxin-6-yl — H F 3-OMe 4-SO₂NHMe VII-262,3-dihydrobenzofuran-5-yl 2-C(O)Nme₂ H F 4-Me 3-SO₂NH₂ VII-272,3-dihydrobenzofuran-5-yl 2-C(O)Nme₂ H F 4-Cl 3-SO₂NH₂ VII-282,3-dihydrobenzopyran-6-yl 4-NH₂ H F — 3-SO₂NH₂ VII-292,3-dihydrobenzopyran-6-yl 4-NH₂ H F — 4-SO₂NH₂ VII-302H-benzo[b][1,4]oxazin-3(4H)-one — H Me Me 3-SO₂NH₂ VII-312H-benzo[b][1,4]oxazin-3(4H)-one — H Me — 4-SO₂NH₂ VII-322H-benzo[b][1,4]oxazin-3(4H)-one — H Me — 3-SO₂NH₂ VII-332H-benzo[b][1,4]thiazin-3(4H)-one Me (N) H Me Me 3-SO₂NH₂ VII-342H-benzo[b][1,4]thiazin-3(4H)-one Me (N) H Me — 4-SO₂NH₂ VII-352H-benzo[b][1,4]thiazin-3(4H)-one Me (N) H Me — 3-SO₂NH₂ VII-363,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 3-oxo H F 4-Me 3-SO₂NH₂ VII-373,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 2,2-diMe, 3-oxo H F 3-OMe4-SO₂NHMe VII-38 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 2,2-diF, 3-oxoH F 4-OMe-5-Me 3-SO₂NH₂ VII-39 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl2,2-diMe, 3-oxo H NH₂ — 3-SO₂NH₂ VII-403,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 3-oxo, 4-Me H F — 4-SO₂NH₂VII-41 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 3-oxo, 4-Me H F —3-SO₂NH₂ VII-42 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 2,2,-diMe,3-oxo, 4-Me H F — 3-SO₂NH₂ VII-433,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl 2,2-diMe, 3-oxo, 4-Me H F —4-SO₂NH₂ VII-44 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 3-oxo H F 4-Me3-SO₂NH₂ VII-45 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 3-oxo, 4-Me H F4-Me 3-SO₂NH₂ VII-46 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 3-oxo,4-Me NC—CH₂— F 4-Me 3-SO₂NH₂ VII-473,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 3-oxo, 4-Me NC—CH₂— F —4-SO₂NH₂ VII-48 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 3-oxo, 4-Me H F— 4-SO₂NH₂ VII-49 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 3-oxo, 4-Me HF — 3-SO₂NH₂ VII-50 3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl 3-oxo, 4-MeH F — 4-SO₂-piperidin-1-yl VII-513,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl 2,2,-diMe, 3-oxo H F —3-SO₂NH₂ VII-52 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl 3-oxo H F —4-SO₂NH₂ VII-53 benzofuran-5-yl 2-CN H F 4-Me 3-SO₂NH₂ VII-54benzofuran-5-yl 2-C(O)NH₂ H F — 3-SO₂NH₂ VII-55 benzomorpholin-6-yl1-((pyridine-3-yl)-CH₂)— H F — 3-SO₂NH₂ VII-56 benzomorpholin-6-yl1-((pyridine-3-yl)-CH₂)— H F 4-Me 3-SO₂NH₂ VII-57 benzothiophen-5-yl — HF 4-Me 3-SO₂NH₂ VII-58 benzothiophen-5-yl — H F — 3-SO₂NH₂ VII-59chroman-6-yl 4-NHAc H F — 4-SO₂NH₂ VII-60 indolin-5-yl1-(methylsulfonyl) H F — 3-SO₂NH₂ VII-61 indolin-5-yl 1-(methylsulfonyl)H F 4-Me 3-SO₂NH₂ VII-62 indolin-5-yl 1-(methylsulfonyl) H F 4-Me3-SO₂NHMe VII-63 indolin-5-yl 1-(methylsulfonyl) H F — 4-SO₂NH₂ VII-64quinolin-2-yl — H F 4-Me 3-SO₂NH₂ VII-65 quinolin-3-yl — H F 4-Me3-SO₂NH₂ VII-66 quinolin-3-yl — H F — 3-SO₂NH₂ VII-67 quinolin-5-yl — HF 4-Me 3-SO₂NH₂ VII-68 quinolin-5-yl — H F — 3-SO₂NH₂ VII-69quinolin-6-yl — H F 4-Me 3-SO₂NH₂ VII-70 quinolin-6-yl — H F — 3-SO₂NH₂VII-71 quinolin-6-yl 2-Me H F 4-Me 3-SO₂NH₂ VII-72 quinolin-6-yl 2-Me HF — 3-SO₂NH₂ VII-73 quinolin-6-yl 2-OH-4-Me H F 4-Me 3-SO₂NH₂ VII-74quinolin-6-yl 2-OH-4-Me H F — 3-SO₂NH₂ VII-75 quinolin-6-yl2-dimethylamino H F 4-Me 3-SO₂NH₂ VII-76 quinolin-6-yl 2-dimethylamino HF — 3-SO₂NH₂ VII-77 quinolin-8-yl — H F 4-Me 3-SO₂NH₂ VII-78quinolin-8-yl — H F — 3-SO₂NH₂ VII-79 quinolin-8-yl — H F 4-F 3-SO₂NH₂VII-80 quinolin-8-yl 2-Me H F 4-Me 3-SO₂NH₂ VII-81 quinolin-8-yl 2-Me HF — 3-SO₂NH₂ VII-82 bicyclo[2.2.1]hept-1-en-4-yl 5-C(O)NH₂ H F 4-Me3-SO₂NH₂ VII-83 bicyclo[2.2.1]hept-1-en-4-yl 5-C(O)NH₂ H F 4-OMe-5-Me3-SO₂NH₂

TABLE VIII

# R¹— -alk-Y- (R²)_(p) (R³)_(q) SO₂ position R⁴ W W position VIII-14-(5-methylisoxazol-3-yl)- —CH₂—O— — — 3 H —C(O)— 4 VIII-2 4-NC——CH₂CH₂— 3-F 5-Me 3 H —CH═N— 4 VIII-3 — — 3-Cl-5-MeO 5-Me 3 H —CH═N— 4

TABLE IX

#

R¹-alk-Y (R²)_(p) (R³)_(q) SO₂NR⁴R⁵ IX-1  1H-indol-5yl — 1-prop-2-ynyl4-Me 3-SO₂NH₂ IX-2  1H-indol-5yl — 1-prop-2-ynyl — 3-SO₂NH₂ IX-3 1H-indol-6-yl — 1-prop-2-ynyl 4-Me 3-SO₂NH₂ IX-4  1H-indol-6-yl —1-prop-2-ynyl — 3-SO₂NH₂ IX-5  indol-5-yl 1-(NC—CH₂)— — 3-SO₂NH₂ IX-6 indol-5-yl 1-(NC—CH₂)— — 4-SO₂NH₂ IX-7  indol-5-yl 1-(NC—CH₂)— 4-Cl3-SO₂NH₂ IX-8  indol-5-yl 1-(NC—CH₂)— 4-Me 3-SO₂NH₂ IX-9  1H-indol-6-yl— 3-C(O)NH₂ 4-Me 3-SO₂NH₂ IX-10 1H-indol-6-yl — 3-C(O)NH₂ 4-Cl 3-SO₂NH₂IX-11 1H-indol-6-yl 3-(NC—CH₂)— 4-Me 3-SO₂NH₂ IX-12 1H-indol-6-yl3-(NC—CH₂)— — — 3-SO₂NH₂ IX-13 1H-indol-5-yl 3-(NC—CH₂)— — — 3-SO₂NH₂IX-14 1H-indol-5-yl 3-(NC—CH₂)— — 4-Me 3-SO₂NH₂ IX-15 1H-indol-7-yl3-(NC—CH₂)— — 3-SO₂NH₂ IX-16 1H-indol-7-yl 3-(NC—CH₂)— 4-Me 3-SO₂NH₂IX-17 1H-indol-6-yl 3-(NC—CH₂)— — 4-(4-Me-piperazin-1-yl) 3-SO₂NH₂ IX-181H-indol-7-yl 3-(NC—CH₂)— — 4-(4-Me-piperazin-1-yl) 3-SO₂NH₂ IX-191H-indol-6-yl 3-(NC—CH₂)— — 4-Me 3-SO₂NH(1- methylpiperadin-4-yl) IX-20indol-5-yl — 1-Me-3-(NC—CH₂)— 4-Me 3-SO₂NH₂ IX-21 benzofuran-5-yl 2-NC —4-Cl 3-SO₂NH₂ IX-22 benzofuran-5-yl 2-NC — 4-isopropyl 3-SO₂NH₂ IX-23phenyl 4-(4-acetyl-piperazin-1-yl)-C⁰— — — 3-SO₂NH₂ IX-24 phenyl4-(4-acetyl-piperazin-1-yl)-C⁰— — 4-Me 3-SO₂NH₂ IX-25 phenyl4-(4-acetyl-piperazin-1-yl)-C⁰— — 4-Me 3-SO₂NHMe IX-26 phenyl4-(4-acetyl-piperazin-1-yl)-C⁰— — — 4-SO₂NH₂ IX-27 phenyl4-(4-acetyl-piperazin-1-yl)-C⁰— — 4-Me 3-SO₂NH₂ IX-28 phenyl4-(4-acetyl-piperazin-1-yl)-C⁰— — — 3-SO₂NH₂ IX-29 phenyl4-(4-methylsulfonyl-piperazin-1-yl)-C⁰— — — 3-SO₂NH₂ IX-30 phenyl4-(4-methylsulfonyl-piperazin-1-yl)-C⁰— — 4-Me 3-SO₂NH₂ IX-31 phenyl4-(4-methylsulfonyl-piperazin-1-yl)-C⁰— — 4-Me 3-SO₂NHMe IX-32 phenyl4-(4-methylsulfonyl-piperazin-1-yl)-C⁰— — — 4-SO₂NH₂ IX-33 phenyl4-(thiomorpholin-1-yl)-C⁰— — 4-Me 3-SO₂NHMe IX-34 phenyl4-(thiomorpholin-1-yl)-C⁰— — — 3-SO₂NH₂ IX-35 phenyl4-(thiomorpholin-1-yl)-C⁰— — 4-Me 3-SO₂NH₂ IX-36 phenyl4-(thiomorpholin-1-yl)-C⁰— — — 4-SO₂NH₂ IX-37 phenyl4-(S,S-dioxo-thiomorpholin-1-yl)-C⁰— — — 3-SO₂NH₂ IX-38 phenyl4-(S,S-dioxo-thiomorpholin-1-yl)-C⁰— — 4-Me 3-SO₂NH₂ IX-39 phenyl4-(S,S-dioxo-thiomorpholin-1-yl)-C⁰— — 4-Me 3-SO₂NHMe IX-40 phenyl4-(S,S-dioxo-thiomorpholin-1-yl)-C⁰— — — 4-SO₂NH₂ IX-41 phenyl4-CH₃C⁰SCH₂C⁰— — — 4-SO₂NH₂ IX-42 phenyl 4-CH₃C⁰SCH₂C⁰— — — 3-SO₂NH₂IX-43 phenyl 4-CH₃C⁰SCH₂C⁰— — 4-Me 3-SO₂NH₂ IX-44 phenyl4-(4-Me-piperazin-1-yl)- 3,5-di-Me — 4-SO₂NH₂ IX-45 pyrrolidin-3-yl 1-—CH₂C⁰— — 4-Me 3-SO₂NH₂ IX-46 thiophen-2-yl 5-MeOC⁰— — 4-Me 3-SO₂NH₂IX-47 thiophen-2-yl 5-MeOC⁰— — — 3-SO₂NH₂ IX-48 thiophen-2-yl 5-MeOC⁰— —4-F 3-SO₂NH₂ IX-49 thiophen-2-yl 5-MeOC⁰— — — 4-SO₂NH₂ IX-50 phenyl —3,4-di-Ome 3-OMe 4-SO₂NHMe IX-51 phenyl — 3,5-di-OMe 3-OMe 4-SO₂NHMeIX-52 phenyl — 3-CF₃-4-Cl 3-OMe 4-SO₂NHMe IX-53 phenyl — 3-Cl-4-OCF₃3-OMe 4-SO₂NHMe IX-54 phenyl 4-pyridin-2-yl-CH₂—O— 3-Cl 4-Me 3-SO₂NHMe

TABLE X # Structure X-1

X-2

X-3

TABLE XI CAS Reg. No. Structure 845817-97-2

841290-42-4

841290-41-3

D. Methods of the Invention

The present invention provides 2,4-substituted pyrimidinediaminecompounds and prodrugs thereof, as described herein, for use in therapyfor the conditions as described herein. The present invention furtherprovides use of the compounds of the present invention in themanufacture of a medicament for the treatment of conditions in whichtargeting of the JAK pathway or inhibition of JAK kinases, particularlyJAK3, may be therapeutically useful. These include conditions where thefunction of lymphocytes, macrophages, or mast cells is involved.Conditions in which targeting of the JAK pathway or inhibition of theJAK kinases, particularly JAK3 may be therapeutically useful include,leukemia, lymphoma, transplant rejection (e.g. pancreas islet transplantrejection), bone marrow transplant applications (e.g. graft-versus-hostdisease)), autoimmune diseases (e.g. rheumatoid arthritis, etc.),inflammation (e.g. asthma, etc.) and other conditions as described ingreater detail herein.

As noted previously, numerous conditions can be treated using the2,4-subsituted pyrimidinediamine compounds, prodrugs thereof, andmethods of treatment as described herein. As used herein, and as wellunderstood in the art, “treatment” is an approach for obtainingbeneficial or desired results, including clinical results. For thepurposes of this invention, beneficial or desired results can includeone or more, but are not limited to, alleviation or amelioration of oneor more symptoms, diminishment of extent of a condition, including adisease, stabilized (i.e., not worsening) state of a condition,including diseases, preventing spread of disease, delay or slowing ofcondition, including disease, progression, amelioration or palliation ofthe condition, including disease, state, and remission (whether partialor total), whether detectable or undetectable. Preferred are compoundsthat are potent and can be administered locally at very low doses, thusminimizing systemic adverse effects.

The compounds described herein are potent and selective inhibitors ofJAK kinases, and particularly selective for cytokine signaling pathwayscontaining JAK3. As a consequence of this activity, the compounds may beused in a variety of in vitro, in vivo and ex vivo contexts to regulateor inhibit JAK kinase activity, signaling cascades in which JAK kinasesplay a role, and the biological responses effected by such signalingcascades. For example, in one embodiment, the compounds may be used toinhibit JAK kinase, either in vitro or in vivo, in virtually any celltype expressing the JAK kinase. For example, in hematopoietic cells, inwhich, for example JAK3 is predominantly expressed. They may also beused to regulate signal transduction cascades in which JAK kinases,particularly JAK3, play a role. Such JAK-dependent signal transductioncascades include, but are not limited to, the signaling cascades ofcytokine receptors that involve the common gamma chain, such as, forexample, the IL-4, IL-7, IL-5, IL-9, IL-15 and IL-21, or IL-2, IL-4,IL-7, IL-9, IL-15 and IL-21 receptor signaling cascades. The compoundsmay also be used in vitro or in vivo to regulate, and in particularinhibit, cellular or biological responses affected by such JAK-dependentsignal transduction cascades. Such cellular or biological responsesinclude, but are not limited to, IL-4/ramos CD23 upregulation, IL-2mediated T-cell proliferation, etc. Importantly, the compounds may beused to inhibit JAK kinases in vivo as a therapeutic approach towardsthe treatment or prevention of diseases mediated, either wholly or inpart, by a JAK kinase activity (referred to herein as “JAK kinasemediated diseases”). Non-limiting examples of JAK kinase mediateddiseases that may be treated or prevented with the compounds, include,but are not limited to allergies, asthma, autoimmune diseases such astransplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin;host versus graft reaction (HVGR), graft versus host reaction (GVHR)etc.), rheumatoid arthritis, and amyotrophic lateral sclerosis, T-cellmediated autoimmune diseases such as multiple sclerosis, psoraiasis andSjogren's syndrome, Type II inflammatory diseases such as vascularinflammation (including vasculitis, arteritis, atherosclerosis andcoronary artery disease), diseases of the central nervous system such asstroke, pulmonary diseases such as bronchitis obliteraus and primarypulmonary hypertension, and solid, delayed Type IV hypersensitivityreactions, and hematologic malignancies such as leukemia and lymphomas.

Examples of diseases that are mediated, at least in part, by JAK kinasesthat can be treated or prevented according to the methods include, butare not limited to, allergies, asthma, autoimmune diseases such astransplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin,host versus graft reaction (HVGR), etc.), rheumatoid arthritis, andamyotrophic lateral sclerosis, multiple sclerosis, psoriasis andSjogren's syndrome, Type II inflammatory disease such as vascularinflammation (including vasculitis, ateritis, atherosclerosis andcoronary artery disease), diseases of the central nervous system such asstroke, pulmonary diseases such as bronchitis obliterous and primary andprimary pulmonary hypertension, delayed or cell-mediated, Type IVhypersensitivity and solid and hematologic malignancies such asleukemias and lyphomas.

JAK kinase mediated disease include, for example, cell proliferativedisorders, such as hematopoietic neoplasms, including lymphoidneoplasms, and myeloid neoplasms. “Cell proliferative disorder” refersto a disorder characterized by abnormal proliferation of cells. Aproliferative disorder does not imply any limitation with respect to therate of cell growth, but merely indicates loss of normal controls thataffect growth and cell division. Thus, in some embodiments, cells of aproliferative disorder can have the same cell division rates as normalcells but do not respond to signals that limit such growth. Within theambit of “cell proliferative disorder” is neoplasm or tumor, which is anabnormal growth of tissue. Cancer refers to any of various malignantneoplasms characterized by the proliferation of cells that have thecapability to invade surrounding tissue and/or metastasize to newcolonization sites.

“Hematopoietic neoplasm” refers to a cell proliferative disorder arisingfrom cells of the hematopoietic lineage. Generally, hematopoiesis is thephysiological process whereby undifferentiated cells or stem cellsdevelop into various cells found in the peripheral blood. In the initialphase of development, hematopoietic stem cells, typically found in thebone marrow, undergo a series of cell divisions to form multipotentprogenitor cells that commit to two main developmental pathways: thelymphoid lineage and the myeloid lineage. The committed progenitor cellsof the myeloid lineage differentiate into three major sub-branchescomprised of the erythroid, megakaryocyte, and granulocyte/monocytedevelopmental pathways. An additional pathway leads to formation ofdendritic cells, which are involved in antigen presentation. Theerythroid lineage gives rise to red blood cells while the megakaryocyticlineage gives rise to blood platelets. Committed cells of thegranulocyte/monocyte lineage split into granulocyte or monocytedevelopmental pathways, the former pathway leading to formation ofneutrophils, eosinophils, and basophils and the latter pathway givingrise to blood monocytes and macrophages.

Committed progenitor cells of the lymphoid lineage develop into the Bcell pathway, T cell pathway, or the non-T/B cell pathway. Similar tothe myeloid lineage, an additional lymphoid pathway appears to give riseto dendritic cells involved in antigen presentation. The B cellprogenitor cell develops into a precursor B cell (pre-B), whichdifferentiates into B cells responsible for producing immunoglobulins.Progenitor cells of the T cell lineage differentiate into precursor Tcells (pre-T) that, based on the influence of certain cytokines, developinto cytotoxic or helper/suppressor T cells involved in cell mediatedimmunity. Non-T/B cell pathway leads to generation of natural killer(NK) cells. Neoplasms of hematopoietic cells can involve cells of anyphase of hematopoiesis, including hematopoietic stem cells, multipotentprogenitor cells, oligopotent committed progenitor cells, precursorcells, and mature differentiated cells. The categories of hematopoieticneoplasms can generally follow the descriptions and diagnostic criteriaemployed by those of skill in the art (see, e.g., InternationalClassification of Disease and Related Health Problems (ICD 10), WorldHealth Organization (2003)). Hematopoietic neoplasms can also becharacterized based on the molecular features, such as cell surfacemarkers and gene expression profiles, cell phenotype exhibited by theaberrant cells, and/or chromosomal aberrations (e.g., deletions,translocations, insertions, etc.) characteristic of certainhematopoietic neoplasms, such as the Philadelphia chromosome found inchronic myelogenous leukemia. Other classifications include NationalCancer Institute Working Formulation (Cancer, 1982, 49:2112-2135) andRevised European-American Lymphoma Classification (REAL).

“Lymphoid neoplasm” refers a proliferative disorder involving cells ofthe lymphoid lineage of hematopoiesis. Lymphoid neoplasms can arise fromhematopoietic stem cells as well as lymphoid committed progenitor cells,precursor cells, and terminally differentiated cells. These neoplasmscan be subdivided based on the phenotypic attributes of the aberrantcells or the differentiated state from which the abnormal cells arise.Subdivisions include, among others, B cell neoplasms, T cell neoplasms,NK cell neoplasms, and Hodgkin's lymphoma.

“Myeloid neoplasm” refers to proliferative disorder of cells of themyeloid lineage of hematopoiesis. Neoplasms can arise from hematopoieticstem cells, myeloid committed progenitor cells, precursor cells, andterminally differentiated cells. Myeloid neoplasms can be subdividedbased on the phenotypic attributes of the aberrant cells or thedifferentiated state from which the abnormal cells arise. Subdivisionsinclude, among others, myeloproliferative diseases,myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes,acute myeloid leukemia, and acute biphenotypic leukemia.

Generally, cell proliferative disorders treatable with the compoundsdisclosed herein relate to any disorder characterized by aberrant cellproliferation. These include various tumors and cancers, benign ormalignant, metastatic or non-metastatic. Specific properties of cancers,such as tissue invasiveness or metastasis, can be targeted using themethods described herein. Cell proliferative disorders include a varietyof cancers, including, among others, breast cancer, ovarian cancer,renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer,pancreatic cancer, lung squamous carcinoma, and adenocarcinoma.

In some embodiments, the cell proliferative disorder treated is ahematopoietic neoplasm, which is aberrant growth of cells of thehematopoietic system. Hematopoietic malignancies can have its origins inpluripotent stem cells, multipotent progenitor cells, oligopotentcommitted progenitor cells, precursor cells, and terminallydifferentiated cells involved in hematopoiesis. Some hematologicalmalignancies are believed to arise from hematopoietic stem cells, whichhave the ability for self renewal. For instance, cells capable ofdeveloping specific subtypes of acute myeloid leukemia (AML) upontransplantation display the cell surface markers of hematopoietic stemcells, implicating hematopoietic stem cells as the source of leukemiccells. Blast cells that do not have a cell marker characteristic ofhematopoietic stem cells appear to be incapable of establishing tumorsupon transplantation (Blaire et al., 1997, Blood 89:3104-3112). The stemcell origin of certain hematological malignancies also finds support inthe observation that specific chromosomal abnormalities associated withparticular types of leukemia can be found in normal cells ofhematopoietic lineage as well as leukemic blast cells. For instance, thereciprocal translocation t(9q34;22q11) associated with approximately 95%of chronic myelogenous leukemia appears to be present in cells of themyeloid, erythroid, and lymphoid lineage, suggesting that thechromosomal aberration originates in hematopoietic stem cells. Asubgroup of cells in certain types of CML displays the cell markerphenotype of hematopoietic stem cells.

Although hematopoietic neoplasms often originate from stem cells,committed progenitor cells or more terminally differentiated cells of adevelopmental lineage can also be the source of some leukemias. Forexample, forced expression of the fusion protein Bcr/Abl (associatedwith chronic myelogenous leukemia) in common myeloid progenitor orgranulocyte/macrophage progenitor cells produces a leukemic-likecondition. Moreover, some chromosomal aberrations associated withsubtypes of leukemia are not found in the cell population with a markerphenotype of hematopoietic stem cells, but are found in a cellpopulation displaying markers of a more differentiated state of thehematopoietic pathway (Turhan et al., 1995, Blood 85:2154-2161). Thus,while committed progenitor cells and other differentiated cells may haveonly a limited potential for cell division, leukemic cells may haveacquired the ability to grow unregulated, in some instances mimickingthe self-renewal characteristics of hematopoietic stem cells (Passegueet al., Proc. Natl. Acad. Sci. USA, 2003, 100:11842-9).

In some embodiments, the hematopoietic neoplasm treated is a lymphoidneoplasm, where the abnormal cells are derived from and/or display thecharacteristic phenotype of cells of the lymphoid lineage. Lymphoidneoplasms can be subdivided into B-cell neoplasms, T and NK-cellneoplasms, and Hodgkin's lymphoma. B-cell neoplasms can be furthersubdivided into precursor B-cell neoplasm and mature/peripheral B-cellneoplasm. Exemplary B-cell neoplasms are precursor B-lymphoblasticleukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) whileexemplary mature/peripheral B-cell neoplasms are B-cell chroniclymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-celllymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma,extranodal marginal zone B-cell lymphoma of MALT type, nodal marginalzone B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, diffuselarge B-cell lymphoma, mediastinal large B-cell lymphoma, primaryeffusion lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia. T-celland Nk-cell neoplasms are further subdivided into precursor T-cellneoplasm and mature (peripheral) T-cell neoplasms. Exemplary precursorT-cell neoplasm is precursor T-lymphoblastic lymphoma/leukemia(precursor T-cell acute lymphoblastic leukemia) while exemplary mature(peripheral) T-cell neoplasms are T-cell prolymphocytic leukemia T-cellgranular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-celllymphoma/leukemia (HTLV-1), extranodal NK/T-cell lymphoma, nasal type,enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, Mycosisfungoides/Sezary syndrome, Anaplastic large-cell lymphoma, T/null cell,primary cutaneous type, Peripheral T-cell lymphoma, not otherwisecharacterized, Angioimmunoblastic T-cell lymphoma, Anaplastic large-celllymphoma, T/null cell, primary systemic type. The third member oflymphoid neoplasms is Hodgkin's lymphoma, also referred to as Hodgkin'sdisease. Exemplary diagnosis of this class that can be treated with thecompounds include, among others, nodular lymphocyte-predominantHodgkin's lymphoma, and various classical forms of Hodgkin's disease,exemplary members of which are Nodular sclerosis Hodgkin's lymphoma(grades 1 and 2), Lymphocyte-rich classical Hodgkin's lymphoma, Mixedcellularity Hodgkin's lymphoma, and Lymphocyte depletion Hodgkin'slymphoma. In various embodiments, any of the lymphoid neoplasms that areassociated with aberrant Syk activity can be treated with the Sykinhibitory compounds.

In some embodiments, the hematopoietic neoplasm treated is a myeloidneoplasm. This group comprises a large class of cell proliferativedisorders involving or displaying the characteristic phenotype of thecells of the myeloid lineage. Myeloid neoplasms can be subdivided intomyeloproliferative diseases, myelodysplastic/myeloproliferativediseases, myelodysplastic syndromes, and acute myeloid leukemias.Exemplary myeloproliferative diseases are chronic myelogenous leukemia(e.g., Philadelphia chromosome positive (t(9;22)(qq34;q11)), chronicneutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilicsyndrome, chronic idiopathic myelofibrosis, polycythemia vera, andessential thrombocythemia. Exemplary myelodysplastic/myeloproliferativediseases are chronic myelomonocytic leukemia, atypical chronicmyelogenous leukemia, and juvenile myelomonocytic leukemia. Exemplarymyelodysplastic syndromes are refractory anemia, with ringedsideroblasts and without ringed sideroblasts, refractory cytopenia(myelodysplastic syndrome) with multilineage dysplasia, refractoryanemia (myelodysplastic syndrome) with excess blasts, 5q-syndrome, andmyelodysplastic syndrome with t(9;12)(q22;p12) (TEL-Syk fusion; see,e.g., Kuno et al., 2001, Blood 97:1050). In various embodiments, any ofthe myeloid neoplasms that are associated with aberrant Syk activity canbe treated with the Syk inhibitory compounds.

In some embodiments, the Syk inhibitory compounds can be used to treatAcute myeloid leukemias (AML), which represent a large class of myeloidneoplasms having its own subdivision of disorders. These subdivisionsinclude, among others, AMLs with recurrent cytogenetic translocations,AML with multilineage dysplasia, and other AML not otherwisecategorized. Exemplary AMLs with recurrent cytogenetic translocationsinclude, among others, AML with t(8;21)(q22;q22), AML1(CBF-alpha)/ETO,Acute promyelocytic leukemia (AML with t(15;17)(q22;q11-12) andvariants, PML/RAR-alpha), AML with abnormal bone marrow eosinophils(inv(16)(p13q22) or t(16;16)(p13;q11), CBFb/MYH11X), and AML with 11q23(MLL) abnormalities. Exemplary AML with multilineage dysplasia are thosethat are associated with or without prior myelodysplastic syndrome.Other acute myeloid leukemias not classified within any definable groupinclude, AML minimally differentiated, AML without maturation, AML withmaturation, Acute myelomonocytic leukemia, Acute monocytic leukemia,Acute erythroid leukemia, Acute megakaryocytic leukemia, Acutebasophilic leukemia, and Acute panmyelosis with myelofibrosis.

Jak mediated diseases also include a variety of autoimmune diseases.Such autoimmune disease include, but are not limited to, thoseautoimmune diseases that are frequently designated as single organ orsingle cell-type autoimmune disorders and those autoimmune disease thatare frequently designated as involving systemic autoimmune disorder.Non-limiting examples of diseases frequently designated as single organor single cell-type autoimmune disorders include: Hashimoto'sthyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritisof pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, autoimmune thrombocytopenia, sympatheticophthalmia, myasthenia gravis, Graves' disease, primary biliarycirrhosis, chronic aggressive hepatitis, ulcerative colitis andmembranous glomerulopathy. Non-limiting examples of diseases oftendesignated as involving systemic autoimmune disorder include: systemiclupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter'ssyndrome, polymyositis-dermatomyositis, systemic sclerosis,polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.Additional autoimmune diseases, which can be f3-cell (humoral) based orT-cell based, include Cogan's syndrome, ankylosing spondylitis,Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onsetdiabetes, and thyroiditis.

The types of autoimmune diseases that may be treated or prevented withJAK inhibitory compounds, as described herein, generally include thosedisorders involving tissue injury that occurs as a result of a humoraland/or cell-mediated response to immunogens or antigens of endogenousand/or exogenous origin. Such diseases are frequently referred to asdiseases involving the nonanaphylactic (i.e., Type II, Type III and/orType IV) hypersensitivity reactions.

Type I hypersensitivity reactions generally result from the release ofpharmacologically active substances, such as histamine, from mast and/orbasophil cells following contact with a specific exogenous antigen. SuchType I reactions play a role in numerous diseases, including allergicasthma, allergic rhinitis, etc. Type II hypersensitivity reactions (alsoreferred to as cytotoxic, cytolytic complement-dependent orcell-stimulating hypersensitivity reactions) result when immunoglobulinsreact with antigenic components of cells or tissue, or with an antigenor hapten that has become intimately coupled to cells or tissue.Diseases that are commonly associated with Type II hypersensitivityreactions include, but are not limited, to autoimmune hemolytic anemia,erythroblastosis fetalis and Goodpasture's disease. Type IIIhypersensitivity reactions, (also referred to as toxic complex, solublecomplex, or immune complex hypersensitivity reactions) result from thedeposition of soluble circulating antigen-immunoglobulin complexes invessels or in tissues, with accompanying acute inflammatory reactions atthe site of immune complex deposition. Non-limiting examples ofprototypical Type III reaction diseases include the Arthus reaction,rheumatoid arthritis, serum sickness, systemic lupus erythematosis,certain types of glomerulonephritis, multiple sclerosis and bullouspemphingoid. Type IV hypersensitivity reactions (frequently calledcellular, cell-mediated, delayed, or tuberculin-type hypersensitivityreactions) are caused by sensitized T-lymphocytes which result fromcontact with a specific antigen. Non-limiting examples of diseases citedas involving Type IV reactions are contact dermatitis and allograftrejection.

Autoimmune diseases associated with any of the above nonanaphylactichypersensitivity reactions may be treated or prevented with inhibitorsof JAK kinase according to the invention described herein. Inparticular, the methods may be used to treat or prevent those autoimmunediseases frequently characterized as single organ or single cell-typeautoimmune disorders including, but not limited to: Hashimoto'sthyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritisof pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, autoimmune thrombocytopenia, sympatheticophthalmia, myasthenia gravis, Graves' disease, primary biliarycirrhosis, chronic aggressive hepatitis, ulcerative colitis andmembranous glomerulopathy, as well as those autoimmune diseasesfrequently characterized as involving systemic autoimmune disorder,which include but are not limited to: systemic lupus erythematosis(SLE), rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome,polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa,multiple sclerosis and bullous pemphigoid.

It will be appreciated by skilled artisans that many of the above-listedautoimmune diseases are associated with severe symptoms, theamelioration of which provides significant therapeutic benefit even ininstances where the underlying autoimmune disease may not beameliorated.

JAK mediated disease also include inflammation and inflammatory diseases(e.g., osteoarthritis, inflammatory bowel disease, ulcerative colitis,Crohn's disease, idiopathic inflammatory bowel disease, irritable bowelsyndrome, spastic colon, etc.), low grade scarring (e.g., scleroderma,increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis,vascular spasms, migraine, reperfusion injury and post myocardialinfarction), and sicca complex or syndrome. All of these diseases may betreated or prevented according to the methods described herein.

In one embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting the JAK kinase with anamount of a compound effective to inhibit an activity of the JAK kinasewherein the compound is selected from the compounds of this invention,as described herein, and the compounds of Table XI (CAS Reg. No.845817-97-2, CAS Reg. No. 841290-42-4, and CAS Reg. No. 841290-41-3).

In another embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting in vitro a JAK3 kinasewith an amount of a compound effective to inhibit an activity of the JAKkinase wherein the compound is selected from the compounds of theinvention, as described herein (including compounds described in TablesI-X), and the compounds of Table XI (CAS Reg. No. 845817-97-2, CAS Reg.No. 841290-42-4, and CAS Reg. No. 841290-41-3). In certain embodimentsof the methods described herein, the method is carried out in vivo.

In a specific embodiment, the compounds can be used to treat and/orprevent rejection in organ and/or tissue transplant recipients (i.e.,treat and/or prevent allorgraft rejection). Allografts may be rejectedthrough either a cell-mediated or humoral immune reaction of therecipient against transplant (histocompability) antigens present on themembranes of the donor's cells. The strongest antigens are governed by acomplex of genetic loci termed human leukocyte group A (HLA) antigens.Together with the ABO blood groups antigens, they are the chieftransplantation antigens detectable in humans. Preferably, the compoundsof the invnetion are used in conjunction with transplant of a kidney,heart, lung, liver, pancreas, small intestine, large intestine, skin, inorder to prevent or ameliorate a host versus graft reaction (HVGR) or agraft versus host reaction (GVHR).

Rejection following transplantation can generally be broken into threecategories: hyperacute, occurring hours to days followingtransplantation; acute, occurring days to months followingtransplantation; and chronic, occurring months to years followingtransplantation.

Hyperacute rejection is caused mainly by the production of hostantibodies that attack the graft tissue. In a hyperacute rejectionreaction, antibodies are observed in the transplant vascular very soonafter transplantation. Shortly thereafter, vascular clotting occurs,leading to ischemia, eventual necrosis and death. The graft infarctionis unresponsive to known immunosuppressive therapies. Because HLAantigens can be identified in vitro, pre-transplant screening is used tosignificantly reduce hyperacute rejection. As a consequence of thisscreening, hyperacute rejection is relative uncommon today.

Acute rejection is thought to be mediated by the accumulation of antigenspecific cells in the graft tissue. The T-cell-mediated immune reactionagainst these antigens (i.e., HVGR or GVHR) is the principle mechanismof acute rejection. Accumulation of these cells leads to damage of thegraft tissue. It is believed that both CD4+ helper T-cells and CD8+cytotoxic T-cells are involved in the process, and that the antigen ispresented by donor and host dendritic cells. The CD4+ helper T-cellshelp recruit other effector cells, such as macrophapges and eosinophils,to the graft. Accessing T-cell activation signal transduction cascades(for example, CD28, CD40L and CD2 cascades) are also involved.

The cell-mediated acute rejection may be reversed in many cases byintensifying immunotherapy. After successful reversal, severely damagedelements of the graft heal by fibrosis and the remainder of the graftappears normal. After resolution of acute rejection, dosages ofimmunosuppressive drugs can be reduced to very low levels.

Chronic rejection, which is a particular problem in renal transplants,often progresses insidiously despite increased immunosuppressivetherapy. It is thought to be due, in large part, to cell-mediated TypeIV hypersensitivity. The pathologic profile differs from that of acuterejection. The arterial endothelium is primarily involved, withextensive proliferation that may gradually occlude the vessel lumen,leading to ischemia, fibrosis, a thickened intima and atheroscleroticchanges. Chronic rejection is mainly due to a progressive obliterationof graft vasculature, and resembles a slow, vasculitic process.

In Type IV hypersensitivity, CD8 cytotoxic T-cells and CD4 helper Tcells recognize either intracellular or extracellular synthesizedantigen when it is complexed, respectively, with either Class I or ClassII MHC molecules. Macrophages function as antigen-presenting cells andrelease IL-1, which promotes proliferation of helper T-cells. HelperT-cells release interferon gamma and IL-2, which together regulatedelayed hyperactivity reactions mediated by macrophage activation andimmunity mediated by T cells. In the case of organ transplant, thecytotoxic T-cells destroy the graft cells on contact.

Since JAK kinases play a critical role in the activation of T-cells, the2,4-substituted pyrimidinediamine compounds described herein can be usedto treat and/or prevent many aspects of transplant rejection, and areparticularly useful in the treatment and/or prevention of rejectionreactions that are mediated, at least in part, by T-cells, such as HVGRor GVHR. The 2,4-substituted pyrimidinediamine compounds can also beused to treat and/or prevent chronic rejection in transplant recipients,and in particular in renal transplant recipients.

In another embodiment, this invention provides a method of treating aT-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound effective to treat the autoimmune disease wherein the compoundis selected from the compounds of the invention, as described herein,and the compounds of Table XI (CAS Reg. No. 845817-97-2, CAS Reg. No.841290-42-4, and CAS Reg. No. 841290-41-3). In certain embodiments ofthe methods the autoimmune disease is multiple sclerosis (MS),psoraisis, or Sjogran's syndrome.

Therapy using the 2,4-substituted pyrimidinediamine compounds describedherein can be applied alone, or it can be applied in combination with oradjunctive to other common immunosuppressive therapies, such as, forexample, mercaptopurine, corticosteroids such as prednisone,methylprednisolone and prednisolone, alkylating agents such ascyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimusand tacrolimus, inhibitors of inosine monophosphate dehydrogenase(IMPDH) such as mycophenolate, mycophenolate mofetil and azathioprine,and agents designed to suppress cellular immunity while leaving therecipient's humoral immunologic response intact, including variousantibodies (for example, antilymphocyte globulin (ALG), antithymocyteglobulin (ATG), monoclonal anti-T-cell antibodies (OKT3)) andirradiation. These various agents can be used in accordance with theirstandard or common dosages, as specified in the prescribing informationaccompanying commercially available forms of the drugs (see also, theprescribing information in the 2006 Edition of The Physician's DeskReference), the disclosures of which are incorporated herein byreference. Azathioprine is currently available from SalixPharmaceuticals, Inc. under the brand name AZASAN; mercaptopurine iscurrently available from Gate Pharmaceuticals, Inc. under the brand namePURINETHOL; prednisone and prednisolone are currently available fromRoxane Laboratories, Inc.; Methyl prednisolone is currently availablefrom Pfizer; sirolimus (rapamycin) is currently available fromWyeth-Ayerst under the brand name RAPAMUNE; tacrolimus is currentlyavailable from Fujisawa under the brand name PROGRAF; cyclosporine iscurrent available from Novartis under the brand dame SANDIMMUNE andAbbott under the brand name GENGRAF; IMPDH inhibitors such asmycophenolate mofetil and mycophenolic acid are currently available fromRoche under the brand name CELLCEPT and Novartis under the brand nameMYFORTIC; azathioprine is currently available from Glaxo Smith Klineunder the brand name IMURAN; and antibodies are currently available fromOrtho Biotech under the brand name ORTHOCLONE, Novartis under the brandname SIMULECT (basiliximab) and Roche under the brand name ZENAPAX(daclizumab).

In another embodiment, the 2,4-substituted pyrimidinediamine compoundscould be administered either in combination or adjunctively with aninhibitor of a Syk kinase. Syk kinase is a tyrosine kinase known to playa critical role in Fcγ receptor signaling, as well as in other signalingcascades, such as those involving B-Cell receptor signaling (Tumer etal., (2000), Immunology Today 21:148-154) and integrins beta(1), beta(2) and beta (3) in neutrophils (Mocsavi et al., (2002), Immunity16:547-558). For example, Syk kinase plays a pivotal role in highaffinity IgE receptor signaling in mast cells that leads to activationand subsequent release of multiple chemical mediators that triggerallergic attacks. However, unlike the JAK kinases, which help regulatethe pathways involved in delayed, or cell-mediated Type IVhypersensitivity reactions, Syk kinase helps regulate the pathwaysinvolved in immediate IgE-mediated, Type I hypersensitivity reactions.Certain compounds that affect the Syk pathway may or may not also affectthe JAK pathways.

Suitable Syk inhibitory compounds are described, for example, in Ser.No. 10/355,543 filed Jan. 31, 2003 (publication no. 2004/0029902); WO03/063794; Ser. No. 10/631,029 filed Jul. 29, 2003; WO 2004/014382; Ser.No. 10/903,263 filed Jul. 30, 2004; PCT/US2004/24716 filed Jul. 30, 2004(WO005/016893); Ser. No. 10/903,870 filed Jul. 30, 2004;PCT/US2004/24920 filed Jul. 30, 2004; Ser. No. 60/630,808 filed Nov. 24,2004; Ser. No. 60/645,424 filed Jan. 19, 2005; and Ser. No. 60/654,620,filed Feb. 18, 2005, the disclosures of which are incorporated herein byreference. The 2,4-substituted pyrimidinediamine described herein andSyk inhibitory compounds could be used alone, or in combination with oneor more conventional transplant rejection treatments, as describedabove.

In a specific embodiment, the 2,4-substituted pyrimidinediaminecompounds can be used to treat or prevent these diseases in patientsthat are either initially non-responsive to (resistant), or that becomenon-responsive to, treatment with a Syk inhibitory compound, or one ofthe other current treatments for the particular disease. The2,4-substituted pyrimidinediamine compounds could also be used incombination with Syk inhibitory compounds in patients that areSyk-compound resistant or non-responsive. Suitable Syk-inhibitorycompounds with which the 2,4-substituted pyrimidinediamine compounds canbe administered are provided supra.

In another embodiment, this invention provides a method of treating aT-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound effective to treat the autoimmune disease wherein the compoundis selected from the compounds of the invention, as described herein,and the compounds of Table XI (CAS Reg. No. 845817-97-2, CAS Reg. No.841290-42-4, and CAS Reg. No. 841290-41-3) and the compound isadministered in combination with, or adjunctively to, a compound thatinhibits Syk kinase with an IC₅₀ in the range of at least 10 μM.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient,comprising administering to the transplant recipient an amount of acompound effective to treat or prevent the rejection wherein thecompound is selected from the compounds of the invention, as describedherein, and the compounds of Table XI (CAS Reg. No. 845817-97-2, CASReg. No. 841290-42-4, and CAS Reg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the rejection is acute rejection, comprising administering to thetransplant recipient an amount of a compound effective to treat orprevent the rejection wherein the compound is selected from thecompounds of the invention, as described herein, and the compounds ofTable XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the rejection is chronic rejection, comprising administering tothe transplant recipient an amount of a compound effective to treat orprevent the rejection wherein the compound is selected from thecompounds of the invention, as described herein, and the compounds ofTable XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the rejection is mediated by HVGR or GVHR, comprisingadministering to the transplant recipient an amount of a compoundeffective to treat or prevent the rejection wherein the compound isselected from the compounds of this invention, as described herein, andthe compounds of Table XI (CAS Reg. No. 845817-97-2, CAS Reg. No.841290-42-4, and CAS Reg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the allograft transplant is selected from a kidney, a heart, aliver and a lung, comprising administering to the transplant recipientan amount of a compound effective to treat or prevent the rejectionwherein the compound is selected from the compounds of this invention,as described herein, and the compounds of Table XI (CAS Reg. No.845817-97-2, CAS Reg. No. 841290-42-4, and CAS Reg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the allograft transplant is selected from a kidney, a heart, aliver and a lung, comprising administering to the transplant recipientan amount of a compound effective to treat or prevent the rejectionwherein the compound is selected from the compounds of the invention, asdescribed herein, and the compounds of Table XI (CAS Reg. No.845817-97-2, CAS Reg. No. 841290-42-4, and CAS Reg. No. 841290-41-3), inwhich the compound is administered in combination with, or adjunctivelyto, another immunosuppressant.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the allograft transplant is selected from a kidney, a heart, aliver and a lung, comprising administering to the transplant recipientan amount of a compound effective to treat or prevent the rejectionwherein the compound is selected from the compounds of the invention, asdescribed herein, and the compounds of Table XI (CAS Reg. No.845817-97-2, CAS Reg. No. 841290-42-4, and CAS Reg. No. 841290-41-3), inwhich the compound is administered in combination with, or adjunctivelyto, another immunosuppressant, in which the immunosuppressant isselected from cyclosporine, tacrolimus, sirolimus, an inhibitor ofIMPDH, mycophenolate, mycophanolate mofetil, an anti-T-Cell antibody andOKT3.

The 2,4-substituted pyrimidinediamine compounds described herein arecytokine moderators of IL-4 signaling. As a consequence, the2,4-substituted pyrimidinediamine compounds could slow the response ofType I hypersensitivity reactions. Thus, in a specific embodiment, the2,4-substituted pyrimidinediamine compounds could be used to treat suchreactions, and therefore the diseases associated with, mediated by orcaused by such hypersensitivity reactions (for example, allergies),prophylactically. For example, an allergy sufferer could take one ormore of the JAK selective compounds described herein prior to expectedexposure to allergens to delay the onset or progress, or eliminatealtogether, an allergic response.

When used to treat or prevent such diseases, the 2,4-substitutedpyrimidinediamine compounds may be administered singly, as mixtures ofone or more 2,4-substituted pyrimidinediamine compounds or in mixture orcombination with other agents useful for treating such diseases and/orthe symptoms associated with such diseases. The 2,4-substitutedpyrimidinediamine compounds may also be administered in mixture or incombination with agents useful to treat other disorders or maladies,such as steroids, membrane stabilizers, 5-lipoxygenase (5LO) inhibitors,leukotriene synthesis and receptor inhibitors, inhibitors of IgE isotypeswitching or IgE synthesis, IgG isotype switching or IgG synthesis,β-agonists, tryptase inhibitors, aspirin, cyclooxygenase (COX)inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4 inhibitors, p38inhibitors, PDE4 inhibitors, and antihistamines, to name a few. The2,4-substituted pyrimidinediamine compounds may be administered per sein the form of prodrugs or as pharmaceutical compositions, comprising anactive compound or prodrug.

In another embodiment, this invention provides a method of treating orpreventing a Type IV hypersensitivity reaction, comprising administeringto a subject an amount of a compound of effective to treat or preventthe hypersensitivity reaction wherein the compound is selected from thecompounds of this invention, as described herein, and the compounds ofTable XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing a Type IV hypersensitivity reaction, which is practicalprophylactically, comprising administering to a subject an amount of acompound of effective to treat or prevent the hypersensitivity reactionwherein the compound is selected from the compounds of this invention,as described herein, and the compounds of Table XI (CAS Reg. No.845817-97-2, CAS Reg. No. 841290-42-4, and CAS Reg. No. 841290-41-3) andis administered prior to exposure to an allergen.

In another embodiment, this invention provides a method of inhibiting asignal transduction cascade in which JAK3 kinase plays a role,comprising contacting a cell expressing a receptor involved in such asignaling cascade with a compound wherein the compound is selected fromthe compounds of this invention, as described herein, and the compoundsof Table XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease wherein the compound is selected from thecompounds of this invention, as described herein, and the compounds ofTable XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, in which the JAK-mediateddisease is HVGR or GVHR, comprising administering to a subject an amountof compound effective to treat or prevent the JAK kinase-mediateddisease wherein the compound is selected from the compounds of theinvention, as described herein, and the compounds of Table XI (CAS Reg.No. 845817-97-2, CAS Reg. No. 841290-42-4, and CAS Reg. No.841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, in which the JAK-mediateddisease is acute allograft rejection, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease wherein the compound is selected from thecompounds of the invention, as described herein, and the compounds ofTable XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3).

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, in which the JAK-mediateddisease is chronic allograft rejection, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease wherein the compound is selected from thecompounds of the invention, as described herein, and the compounds ofTable XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3).

Active compounds of the invention typically inhibit the JAK/Statpathway. The activity of a specified compound as an inhibitor of a JAKkinase may be assessed in vitro or in vivo. In some embodiments, theactivity of a specified compound can be tested in a cellular assay.Suitable assays include assays that determine inhibition of either thephosphorylation activity or ATPase activity of a JAK kinase. Thus, acompound is said to inhibit an activity of a JAK kinase if it inhibitsthe phosphorylation or ATPase activity of a JAK kinase with an IC₅₀ ofabout 20 μM or less.

One means of assaying for such inhibition is detection of the effect ofthe 2,4-substituted pyrimidinediamine compounds on the upregulation ofdownstream gene products. In the Ramos/IL4 assay, B-cells are stimulatedwith the cytokine Interleukin-4 (IL-4) leading to the activation of theJAK/Stat pathway through phosphorylation of the JAK family kinases, JAK1and JAK3, which in turn phosphorylate and activate the transcriptionfactor Stat-6. One of the genes upregulated by activated Stat-6 is thelow affinity IgE receptor, CD23. To study the effect of inhibitors(e.g., the 2,4-substituted pyrimindinediamine compounds describedherein) on the JAK1 and JAK3 kinases, human Ramos B cells are stimulatedwith human IL-4. Twenty to 24 hours post stimulation, cells are stainedfor upregulation of CD23 and analyzed using flow cytometry (FACS). Areduction of the amount of CD23 present compared to control conditionsindicates the test compound actively inhibits the JAK kinase pathway. Anexemplary assay of this type is described in greater detail in Example41

The activity of the active compounds of the invention may further becharacterized by assaying the effect of the 2,4-substitutedpyrimidinediamine compounds described herein on the proliferativeresponse of primary human T-cells. In this assay, primary human T-cellsderived from peripheral blood and pre-activated through stimulation ofthe T-cell receptor and CD28, proliferate in culture in response to thecytokine Interleukin-2 (IL-2). This proliferative response is dependenton the activation of JAK1 and JAK3 tyrosine kinases, which phosphorylateand activate the transcription factor Stat-5. The primary human T-cellsare incubated with the 2,4-substituted pyrimidinediamine compounds inthe presence of IL-2 for 72 hours and at the assay endpointintracellular ATP concentrations are measured to assess cell viability.A reduction in cell proliferation compared to control conditions isindicative of inhibition of the JAK kinase pathway. An exemplary assayof this type is described in greater detail in Example 42

The activity of the compounds of the invention may additionally becharacterized by assaying the effect of the 2,4-substitutedpyrimidinediamine compounds described herein on A549 lung epithelialcells and U937 cells. A549 lung epithelial cells and U937 cellsup-regulate ICAM-1 (CD54) surface expression in response to a variety ofdifferent stimuli. Therefore, using ICAM-1 expression as readout, testcompound effects on different signaling pathways can be assessed in thesame cell type. Stimulation with IL-1β through the IL-1β receptoractivates the TRAF6/NFκB pathway resulting in up-regulation of ICAM-1.IFNγ induces ICAM-1 up-regulation through activation of the JAK1/JAK2pathway. The up-regulation of ICAM-1 can be quantified by flow cytometryacross a compound dose curve and EC₅₀ values are calculated. Anexemplary assays of this type are described in greater detail inExamples 43 and 44

Active compounds as described herein generally inhibit the JAK kinasepathway with an IC₅₀ in the range of about 1 mM or less, as measured inthe assays described herein. Of course, skilled artisans will appreciatethat compounds which exhibit lower IC₅₀s, for example on the order of100 μM, 75 μM, 50 μM, 40 μM, 30 μM, 20 μM, 15 μM, 10 μM, 5 μM, 1 μM, 500nM, 100 nM, 10 nM, 1 nM, or even lower, may be particularly useful intherapeutic applications. In instances where activity specific to aparticular cell type is desired, the compound may be assayed foractivity with the desired cell type and counter-screened for a lack ofactivity against other cell types. The desired degree of “inactivity” insuch counter screens, or the desired ratio of activity vs. inactivitymay vary for different situations, and may be selected by the user.

The 2,4-substituted pyrimidinediamine active compounds also typicallyinhibit IL-4 stimulated expression of CD23 in B-cells with an IC₅₀ inthe range of about 20 μM or less, typically in the range of about 10 μM,500 nM, 100 nM, 10 nM, 1 nM, or even lower. A suitable assay that can beused is the assay described in Example 41 “Assay for Ramos B-Cell LineStimulated with IL-4.” In certain embodiments, the active2,4-substituted pyrimidinediamine compounds have an IC₅₀ of less than orequal to 5 μM, greater than 5 μM but less than 20 μM, greater than 20μM, or greater than 20 μM but less than 50 μM in the assay described inExample 41

Additionally, the 2,4-substituted pyrimidinediamine active compoundsalso typically inhibit an activity of an human primary T-cells with anIC₅₀ in the range of about 20 μM or less, typically in the range ofabout 10 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower. The IC₅₀against human primary T-cells can be determined in a standard in vitroassay with isolated human primary T-cells. A suitable assay that can beused is the assay described in Example 42 “Primary Human T-cellProliferation Assay Stimulated with IL-2.” In certain embodiments, theactive 2,4-substituted pyrimidinediamine compounds have an IC₅₀ of lessthan or equal to 5 μM, greater than 5 μM but less than 20 μM, greaterthan 20 μM, or greater than 20 μM but less than 50 μM in the assaydescribed in Example 42

The 2,4-substituted pyrimidinediamine active compounds also typicallyinhibit expression of ICAM1 (CD54) induced by IFNγ exposure in U937 orA549 cells with an IC₅₀ in the range of about 20 μM or less, typicallyin the range of about 10 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower.The IC₅₀ against expression of ICAM (CD54) in IFNγ stimulated cells canbe determined in a functional cellular assay with an isolated A549 orU937 cell line. Suitable assays that can be used are the assaysdescribed in Examples 43 and 44 “A549 Epithelial Line Stimulated withIFNγ,” or “U937 IFNγ ICAM1 FACS Assay,” respectively. In certainembodiments, the active 2,4-substituted pyrimidinediamine compounds havean IC₅₀ of less than or equal to 20 μM, greater than 20 μM, or greaterthan 20 μM but less than 50 μM in the assays described in Example 43 orExample 44

E. Pharmaceutical Compositions of the Invention

Pharmaceutical compositions comprising the 2,4-substitutedpyrimidinediamine compounds described herein (or prodrugs thereof) maybe manufactured by means of conventional mixing, dissolving,granulating, dragee-making levigating, emulsifying, encapsulating,entrapping or lyophilization processes. The compositions may beformulated in conventional manner using one or more physiologicallyacceptable carriers, diluents, excipients or auxiliaries whichfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically.

The 2,4-substituted pyrimidinediamine compound or prodrug may beformulated in the pharmaceutical compositions per se, or in the form ofa hydrate, solvate, N-oxide or pharmaceutically acceptable salt, asdescribed herein. Typically, such salts are more soluble in aqueoussolutions than the corresponding free acids and bases, but salts havinglower solubility than the corresponding free acids and bases may also beformed.

In one embodiment, this invention provides a pharmaceutical formulationcomprising a compound selected from the compounds of the invention, asdescribed herein, and the compounds of Table XI (CAS Reg. No.845817-97-2, CAS Reg. No. 841290-42-4, and CAS Reg. No. 841290-41-3) ora prodrug thereof, and at least one pharmaceutically acceptableexcipient, diluent, preservative, or stabilizer, or mixtures thereof.

In another embodiment, the methods may be practiced as a therapeuticapproach towards the treatment of the conditions described herein. Thus,in a specific embodiment, the 2,4-substituted pyrimidinediaminecompounds (and the various forms described herein, includingpharmaceutical formulations comprising the compounds (in the variousforms)) may be used to treat the conditions described herein in animalsubjects, including humans. The methods generally comprise administeringto the subject an amount of a compound of the invention, or a salt,prodrug, hydrate or N-oxide thereof, effective to treat the condition.In one embodiment, the subject is a mammal, including, but not limitedto, bovine, horse, feline, canine, rodent, or primate. In anotherembodiment, the subject is a human.

The compounds can be provided in a variety of formulations and dosages.The compounds may be provided in a pharmaceutically acceptable formincluding, where the compound or prodrug may be formulated in thepharmaceutical compositions per se, or in the form of a hydrate,solvate, N-oxide or pharmaceutically acceptable salt, as describedherein. Typically, such salts are more soluble in aqueous solutions thanthe corresponding free acids and bases, but salts having lowersolubility than the corresponding free acids and bases may also beformed. It is to be understood that reference to the compound,2,4-substituted pyrimidinediamine compound, or “active” in discussionsof formulations is also intended to include, where appropriate as knownto those of skill in the art, formulation of the prodrugs of the2,4-substituted pyrimidinediamine compounds.

In one embodiment, the compounds are provided as non-toxicpharmaceutically acceptable salts, as noted previously. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts such as those formed with hydrochloric acid,fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid,acetic acid, citric acid, tartaric acid, carbonic acid or phosphoricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The pharmaceutically acceptable salts of the present invention may beformed by conventional means, such as by reacting the free base form ofthe product with one or more equivalents of the appropriate acid in asolvent or medium in which the salt is insoluble, or in a solvent suchas water which is removed in vacuo or by freeze drying or by exchangingthe anions of an existing salt for another anion on a suitable ionexchange resin.

The present invention includes within its scope solvates of the2,4-substituted pyrimidinediamine compounds and salts thereof, forexample, hydrates.

The 2,4-substituted pyrimidinediamine compounds may have one or moreasymmetric centers, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The 2,4-substituted pyrimidinediamine compounds may be administered byoral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,ICV, intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual,urethral (e.g., urethral suppository) or topical routes ofadministration (e.g., gel, ointment, cream, aerosol, etc.) and may beformulated, alone or together, in suitable dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants, excipients and vehicles appropriate for each route ofadministration. In addition to the treatment of warm-blooded animalssuch as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc.,the compounds of the invention may be effective in humans.

The pharmaceutical compositions for the administration of the2,4-substituted pyrimidinediamine compounds may conveniently bepresented in dosage unit form and may be prepared by any of the methodswell known in the art of pharmacy. The pharmaceutical compositions canbe, for example, prepared by uniformly and intimately bringing theactive ingredient into association with a liquid carrier or a finelydivided solid carrier or both, and then, if necessary, shaping theproduct into the desired formulation. In the pharmaceutical compositionthe active object compound is included in an amount sufficient toproduce the desired therapeutic effect. For example, pharmaceuticalcompositions of the invention may take a form suitable for virtually anymode of administration, including, for example, topical, ocular, oral,buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc.,or a form suitable for administration by inhalation or insufflation.

For topical administration, the JAK-selective compound(s) or prodrug(s)may be formulated as solutions, gels, ointments, creams, suspensions,etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, etc., before use.To this end, the active compound(s) may be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings. Additionally,the pharmaceutical compositions containing the 2,4-substitutedpyrimidinediamine as active ingredient or prodrug thereof in a formsuitable for oral use, may also include, for example, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient (including prodrug)in admixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents (e.g., corn starch, or alginic acid); bindingagents (e.g. starch, gelatin or acacia); and lubricating agents (e.g.magnesium stearate, stearic acid or talc). The tablets may be uncoatedor they may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the techniques described in the U.S. Pat. Nos.4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to form osmotictherapeutic tablets for control release. The pharmaceutical compositionsof the invention may also be in the form of oil-in-water emulsions.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases such as cocoa butteror other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. The2,4-substituted pyrimidinediamine compounds may also be administered inthe form of suppositories for rectal or urethral administration of thedrug. In particular embodiments, the compounds may be formulated asurethral suppositories, for example, for use in the treatment offertility conditions, particularly in males, e.g., for the treatment oftesticular dysfunction.

According to the invention, 2,4-substituted pyrimidinediamine compoundscan be used for manufacturing a composition or medicament, includingmedicaments suitable for rectal or urethral administration. Theinvention also relates to methods for manufacturing compositionsincluding 2,4-substituted pyrimidinediamine compounds in a form that issuitable for urethral or rectal administration, including suppositories.

For topical use, creams, ointments, jellies, gels, solutions orsuspensions, etc., containing the 2,4-substituted pyrimidinediaminecompounds may be employed. In certain embodiments, the 2,4-substitutedpyrimidinediamine compounds may be formulated for topical administrationwith polyethylene glycol (PEG). These formulations may optionallycomprise additional pharmaceutically acceptable ingredients such asdiluents, stabilizers and/or adjuvants. In particular embodiments, thetopical formulations are formulated for the treatment of allergicconditions and/or skin conditions including psoriasis, contactdermatitis and atopic dermatitis, among others described herein.

According to the invention, 2,4-substituted pyrimidinediamine compoundscan be used for manufacturing a composition or medicament, includingmedicaments suitable for topical administration. The invention alsorelates to methods for manufacturing compositions including2,4-substituted pyrimidinediamine compounds in a form that is suitablefor topical administration.

According to the present invention, 2,4-substituted pyrimidinediaminecompounds can also be delivered by any of a variety of inhalationdevices and methods known in the art, including, for example: U.S. Pat.No. 6,241,969; U.S. Pat. No. 6,060,069; U.S. Pat. No. 6,238,647; U.S.Pat. No. 6,335,316; U.S. Pat. No. 5,364,838; U.S. Pat. No. 5,672,581;WO96/32149; WO95/24183; U.S. Pat. No. 5,654,007; U.S. Pat. No.5,404,871; U.S. Pat. No. 5,672,581; U.S. Pat. No. 5,743,250; U.S. Pat.No. 5,419,315; U.S. Pat. No. 5,558,085; WO98/33480; U.S. Pat. No.5,364,833; U.S. Pat. No. 5,320,094; U.S. Pat. No. 5,780,014; U.S. Pat.Nos. 5,658,878; 5,518,998; 5,506,203; U.S. Pat. No. 5,661,130; U.S. Pat.No. 5,655,523; U.S. Pat. No. 5,645,051; U.S. Pat. No. 5,622,166; U.S.Pat. No. 5,577,497; U.S. Pat. No. 5,492,112; U.S. Pat. No. 5,327,883;U.S. Pat. No. 5,277,195; U.S. Pat. App. No. 20010041190; U.S. Pat. App.No. 20020006901; and U.S. Pat. App. No. 20020034477.

Included among the devices which may be used to administer particularexamples of the 2,4-substituted pyrimidinediamine compounds are thosewell-known in the art, such as, metered dose inhalers, liquidnebulizers, dry powder inhalers, sprayers, thermal vaporizers, and thelike. Other suitable technology for administration of particular2,4-substituted pyrimidinediamine compounds includes electrohydrodynamicaerosolizers.

In addition, the inhalation device is preferably practical, in the senseof being easy to use, small enough to carry conveniently, capable ofproviding multiple doses, and durable. Some specific examples ofcommercially available inhalation devices are Turbohaler (Astra,Wilmington, Del.), Rotahaler (Glaxo, Research Triangle Park, N.C.),Diskus (Glaxo, Research Triangle Park, N.C.), the Ultravent nebulizer(Mallinckrodt), the Acorn II nebulizer (Marquest Medical Products,Totowa, N.J.) the Ventolin metered dose inhaler (Glaxo, ResearchTriangle Park, N.C.), or the like. In one embodiment, 2,4-substitutedpyrimidinediamine compounds can be delivered by a dry powder inhaler ora sprayer.

As those skilled in the art will recognize, the formulation of2,4-substituted pyrimidinediamine compounds, the quantity of theformulation delivered, and the duration of administration of a singledose depend on the type of inhalation device employed as well as otherfactors. For some aerosol delivery systems, such as nebulizers, thefrequency of administration and length of time for which the system isactivated will depend mainly on the concentration of 2,4-substitutedpyrimidinediamine compounds in the aerosol. For example, shorter periodsof administration can be used at higher concentrations of2,4-substituted pyrimidinediamine compounds in the nebulizer solution.Devices such as metered dose inhalers can produce higher aerosolconcentrations, and can be operated for shorter periods to deliver thedesired amount of 2,4-substituted pyrimidinediamine compounds in someembodiments. Devices such as dry powder inhalers deliver active agentuntil a given charge of agent is expelled from the device. In this typeof inhaler, the amount of 2,4-substituted pyrimidinediamine compounds ina given quantity of the powder determines the dose delivered in a singleadministration. The formulation of 2,4-substituted pyrimidinediamine isselected to yield the desired particle size in the chosen inhalationdevice.

Formulations of 2,4-substituted pyrimidinediamine compounds foradministration from a dry powder inhaler may typically include a finelydivided dry powder containing 2,4-substituted pyrimidinediaminecompounds, but the powder can also include a bulking agent, buffer,carrier, excipient, another additive, or the like. Additives can beincluded in a dry powder formulation of 2,4-substitutedpyrimidinediamine compounds, for example, to dilute the powder asrequired for delivery from the particular powder inhaler, to facilitateprocessing of the formulation, to provide advantageous powder propertiesto the formulation, to facilitate dispersion of the powder from theinhalation device, to stabilize to the formulation (e.g., antioxidantsor buffers), to provide taste to the formulation, or the like. Typicaladditives include mono-, di-, and polysaccharides; sugar alcohols andother polyols, such as, for example, lactose, glucose, raffinose,melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, orcombinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, or lecithin; or the like.

The present invention also relates to a pharmaceutical compositionincluding 2,4-substituted pyrimidinediamine compounds suitable foradministration by inhalation. According to the invention,2,4-substituted pyrimidinediamine compounds can be used formanufacturing a composition or medicament, including medicamentssuitable for administration by inhalation. The invention also relates tomethods for manufacturing compositions including 2,4-substitutedpyrimidinediamine compounds in a form that is suitable foradministration, including administration by inhalation. For example, adry powder formulation can be manufactured in several ways, usingconventional techniques, such as described in any of the publicationsmentioned above and incorporated expressly herein by reference, and forexample, Baker, et al., U.S. Pat. No. 5,700,904, the entire disclosureof which is incorporated expressly herein by reference. Particles in thesize range appropriate for maximal deposition in the lower respiratorytract can be made by micronizing, milling, or the like. And a liquidformulation can be manufactured by dissolving the 2,4-substitutedpyrimidinediamine compounds in a suitable solvent, such as water, at anappropriate pH, including buffers or other excipients.

Pharmaceutical compositions comprising the 2,4-substitutedpyrimidinediamine compounds described herein (or prodrugs thereof) maybe manufactured by means of conventional mixing, dissolving,granulating, dragee-making levigating, emulsifying, encapsulating,entrapping or lyophilization processes. The compositions may beformulated in conventional manner using one or more physiologicallyacceptable carriers, diluents, excipients or auxiliaries whichfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically.

For ocular administration, the 2,4-substituted pyrimidinediaminecompound(s) or prodrug(s) may be formulated as a solution, emulsion,suspension, etc. suitable for administration to the eye. A variety ofvehicles suitable for administering compounds to the eye are known inthe art. Specific non-limiting examples are described in U.S. Pat. No.6,261,547; U.S. Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat.No. 5,800,807; U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S.Pat. No. 5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033;U.S. Pat. No. 4,882,150; and U.S. Pat. No. 4,738,851.

For prolonged delivery, the 2,4-substituted pyrimidinediaminecompound(s) or prodrug(s) can be formulated as a depot preparation foradministration by implantation or intramuscular injection. The activeingredient may be formulated with suitable polymeric or hydrophobicmaterials (e.g., as an emulsion in an acceptable oil) or ion exchangeresins, or as sparingly soluble derivatives, e.g., as a sparinglysoluble salt. Alternatively, transdermal delivery systems manufacturedas an adhesive disc or patch which slowly releases the activecompound(s) for percutaneous absorption may be used. To this end,permeation enhancers may be used to facilitate transdermal penetrationof the active compound(s). Suitable transdermal patches are described infor example, U.S. Pat. No. 5,407,713.; U.S. Pat. No. 5,352,456; U.S.Pat. No. 5,332,213; U.S. Pat. No. 5,336,168; U.S. Pat. No. 5,290,561;U.S. Pat. No. 5,254,346; U.S. Pat. No. 5,164,189; U.S. Pat. No.5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat. No. 5,087,240; U.S. Pat.No. 5,008,110; and U.S. Pat. No. 4,921,475.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

The 2,4-substituted pyrimidinediamine compound(s) or prodrug(s)described herein, or compositions thereof, will generally be used in anamount effective to achieve the intended result, for example in anamount effective to treat or prevent the particular condition beingtreated. The compound(s) may be administered therapeutically to achievetherapeutic benefit or prophylactically to achieve prophylactic benefit.By therapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying disorder suchthat the patient reports an improvement in feeling or condition,notwithstanding that the patient may still be afflicted with theunderlying disorder. For example, administration of a compound to apatient suffering from an allergy provides therapeutic benefit not onlywhen the underlying allergic response is eradicated or ameliorated, butalso when the patient reports a decrease in the severity or duration ofthe symptoms associated with the allergy following exposure to theallergen. As another example, therapeutic benefit in the context ofasthma includes an improvement in respiration following the onset of anasthmatic attack, or a reduction in the frequency or severity ofasthmatic episodes. As another specific example, therapeutic benefit inthe context of transplantation rejection includes the ability toalleviate an acute rejection episode, such as for example, HVGR or GVHR,or the ability to prolong the time period between onset of acuterejection episodes and/or onset of chronic rejection. Therapeuticbenefit also includes halting or slowing the progression of the disease,regardless of whether improvement is realized.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular condition being treated,the mode of administration, the severity of the condition being treatedand the age and weight of the patient, the bioavailability of theparticular active compound, etc. Determination of an effective dosage iswell within the capabilities of those skilled in the art.

As known by those of skill in the art, the preferred dosage of2,4-substituted pyrimidinediamine compounds will also depend on the age,weight, general health and severity of the condition of the individualbeing treated. Dosage may also need to be tailored to the sex of theindividual and/or where administered by inhalation, the lung capacity ofthe individual. Dosage may also be tailored to individuals sufferingfrom more than one condition or those individuals who have additionalconditions which affect lung capacity and the ability to breathenormally, for example, emphysema, bronchitis, pneumonia, respiratoryinfections, etc. Dosage, and frequency of administration of thecompounds or prodrugs thereof, will also depend on whether the compoundsare formulated for treatment of acute episodes of a condition or for theprophylactic treatment of a disorder. For example, acute episodes ofallergic conditions, including allergy-related asthma, transplantrejection, etc. A skilled practitioner will be able to determine theoptimal dose for a particular individual.

For prophylactic administration, the compound may be administered to apatient at risk of developing one of the previously describedconditions. For example, if it is unknown whether a patient is allergicto a particular drug, the compound may be administered prior toadministration of the drug to avoid or ameliorate an allergic responseto the drug. Alternatively, prophylactic administration may be appliedto avoid the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a compound may be administered to anallergy sufferer prior to expected exposure to the allergen. Compoundsmay also be administered prophylactically to healthy individuals who arerepeatedly exposed to agents known to one of the above-describedmaladies to prevent the onset of the disorder. For example, a compoundmay be administered to a healthy individual who is repeatedly exposed toan allergen known to induce allergies, such as latex, in an effort toprevent the individual from developing an allergy. Alternatively, acompound may be administered to a patient suffering from asthma prior topartaking in activities which trigger asthma attacks to lessen theseverity of, or avoid altogether, an asthmatic episode.

In the context of transplant rejection, the compound may be administeredwhile the patient is not having an acute rejection reaction to avoid theonset of rejection and/or prior to the appearance of clinicalindications of chronic rejection.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, etc. Determination of an effectivedosage is well within the capabilities of those skilled in the art.

Effective dosages may be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals may be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in asin vitro assay. Calculating dosages to achieve such circulating blood orserum concentrations taking into account the bioavailability of theparticular compound is well within the capabilities of skilled artisans.For guidance, the reader is referred to Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, andthe references cited therein.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21Suppl):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Suitable animal models of allergic conjunctivitis are described inCarreras et al., (1993), Br. J. Ophthalmol. 77(8):509-514; Saiga et al.,(1992), Ophthalmic Res. 24(1):45-50; and Kunert et al., (2001), Invest.Ophthalmol. Vis. Sci. 42(11):2483-2489. Suitable animal models ofsystemic mastocytosis are described in O'Keefe et al., (1987), J. Vet.Intern. Med. 1(2):75-80 and Bean-Knudsen et al., (1989), Vet. Pathol.26(1):90-92. Suitable animal models of hyper IgE syndrome are describedin Claman et al., (1990), Clin. Immunol. Immunopathol. 56(1):46-53.Suitable animal models of B-cell lymphoma are described in Hough et al.,(1998), Proc. Natl. Acad. Sci. USA 95:13853-13858 and Hakim et al.,(1996), J. Immunol. 157(12):5503-5511. Suitable animal models of atopicdisorders such as atopic dermatitis, atopic eczema and atopic asthma aredescribed in Chan et al., (2001), J. Invest. Dermatol. 117(4):977-983and Suto et al., (1999), Int. Arch. Allergy Immunol. 120(Suppl 1):70-75.Suitable animal models of transplant rejection, such as models of HVGRare described in O'Shea et al., (2004), Nature Reviews Drug Discovery3:555-564; Cetkovic-Curlje & Tibbles, (2004), Current PharmaceuticalDesign 10:1767-1784; and Chengelian et al., (2003), Science 302:875-878.Ordinarily skilled artisans can routinely adapt such information todetermine dosages suitable for human administration.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration and variousfactors discussed above. Dosage amount and interval may be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. For example,the compounds may be administered once per week, several times per week(e.g., every other day), once per day or multiple times per day,depending upon, among other things, the mode of administration, thespecific indication being treated and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) may be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The foregoing disclosure pertaining to the dosage requirements for the2,4-sbustituted pyrimidinediamine compounds is pertinent to dosagesrequired for prodrugs, with the realization, apparent to the skilledartisan, that the amount of prodrug(s) administered will also dependupon a variety of factors, including, for example, the bioavailabilityof the particular prodrug(s) the conversation rate and efficiency intoactive drug compound under the selected route of administration, etc.Determination of an effective dosage of prodrug(s) for a particular useand mode of administration is well within the capabilities of thoseskilled in the art.

Effective dosages may be estimated initially from in vitro activity andmetabolism assays. For example, an initial dosage of prodrug for use inanimals may be formulated to achieve a circulating blood or serumconcentration of the metabolite active compound that is at or above anIC₅₀ of the particular compound as measured in as in vitro assay, suchas the in vitro CHMC or BMMC and other in vitro assays described in U.S.application Ser. No. 10/355,543 filed Jan. 31, 2003 (US2004/0029902A1),international application Serial No. PCT/US03/03022 filed Jan. 31, 2003(WO 03/063794), U.S. application Ser. No. 10/631,029 filed Jul. 29,2003, international application Serial No. PCT/US03/24087(WO2004/014382), U.S. application Ser. No. 10/903,263 filed Jul. 30,2004, and international application Serial No. PCT/US2004/24716(WO005/016893). Calculating dosages to achieve such circulating blood orserum concentrations taking into account the bioavailability of theparticular prodrug via the desired route of administration is wellwithin the capabilities of skilled artisans. For guidance, the reader isreferred to Fingl & Woodbury, “General Principles,” In: Goodman andGilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46,latest edition, Pagamonon Press, and the references cited therein.

Also provided are kits for administration of the 2,4-substitutedpyrimidinediamine, prodrug thereof or pharmaceutical formulationscomprising the compound, that may include a dosage amount of at leastone 2,4-substituted pyrimidinediamine or a composition comprising atleast one 2,4-substituted pyrimidinediamine as disclosed herein. Kitsmay further comprise suitable packaging and/or instructions for use ofthe compound. Kits may also comprise a means for the delivery of the atleast one 2,4-substituted pyrimidinediamine or compositions comprisingat least one 2,4-substituted pyrimidinediamine, such as an inhaler,spray dispenser (e.g. nasal spray), syringe for injection or pressurepack for capsules, tables, suppositories, or other device as describedherein.

Additionally, the compounds of the present invention may be assembled inthe form of kits. The kit provides the compound and reagents to preparea composition for administration. The composition may be in a dry orlyophilized form, or in a solution, particularly a sterile solution.When the composition is in a dry form, the reagent may comprise apharmaceutically acceptable diluent for preparing a liquid formulation.The kit may contain a device for administration or for dispensing thecompositions, including, but not limited to syringe, pipette,transdermal patch, or inhalant.

The kits may include other therapeutic compounds for use in conjunctionwith the compounds described herein. In one embodiment, the therapeuticagents are immunosuppressant or anti-allergan compounds. These compoundsmay be provided in a separate form, or mixed with the compounds of thepresent invention.

The kits will include appropriate instructions for preparation andadministration of the composition, side effects of the compositions, andany other relevant information. The instructions may be in any suitableformat, including, but not limited to, printed matter, videotape,computer readable disk, or optical disc.

In one embodiment, this invention provides a kit comprising a compoundselected from the compounds of the invention, as described herein, andthe compounds of Table XI (CAS Reg. No. 845817-97-2, CAS Reg. No.841290-42-4, and CAS Reg. No. 841290-41-3) or a prodrug thereof,packaging and instructions for use.

In another embodiment, this invention provides a kit comprising thepharmaceutical formulation comprising a compound selected from thecompounds of the invention, as described herein, and the compounds ofTable XI (CAS Reg. No. 845817-97-2, CAS Reg. No. 841290-42-4, and CASReg. No. 841290-41-3) or a prodrug thereof, and at least onepharmaceutically acceptable excipient, diluent, preservative, orstabilizer, or mixtures thereof, packaging, and instructions for use.

In another aspect of the invention, kits for treating an individual whosuffers from or is susceptible to the conditions described herein areprovided, comprising a container comprising a dosage amount of an2,4-substituted pyrimidinediamine or composition as disclosed herein,and instructions for use. The container may be any of those known in theart and appropriate for storage and delivery of oral, intravenous,topical, rectal, urethral, or inhaled formulations.

Kits may also be provided that contain sufficient dosages of the2,4-substituted pyrimidinediamine or composition to provide effectivetreatment for an individual for an extended period, such as a week, 2weeks, 3, weeks, 4 weeks, 6 weeks or 8 weeks or more.

F. General Synthesis of the Compounds of the Invention

The 2,4-pyrimidinediamine compounds and prodrugs of the invention may besynthesized via a variety of different synthetic routes usingcommercially available starting materials and/or starting materialsprepared by conventional synthetic methods. Suitable exemplary methodsthat may be routinely adapted to synthesize the 2,4-pyrimidinediaminecompounds and prodrugs of the invention are found in U.S. Pat. No.5,958,935, the disclosure of which is incorporated herein by reference.Specific examples describing the synthesis of numerous2,4-pyrimidinediamine compounds and prodrugs, as well as intermediatestherefore, are described in copending U.S. application Ser. No.10/355,543, filed Jan. 31, 2003 (US2004/0029902A1), the contents ofwhich are incorporated herein by reference. Suitable exemplary methodsthat may be routinely used and/or adapted to synthesize active2,4-substituted pyrimidinediamine compounds can also be found ininternational application Serial No. PCT/US03/03022 filed Jan. 31, 2003(WO 03/063794), U.S. application Ser. No. 10/631,029 filed Jul. 29,2003, international application Serial No. PCT/US03/24087(WO2004/014382), U.S. application Ser. No. 10/903,263 filed Jul. 30,2004, and international application Serial No. PCT/US2004/24716(WO005/016893), the disclosures of which are incorporated herein byreference. All of the compounds described herein (including prodrugs)may be prepared by routine adaptation of these methods.

Specific exemplary synthetic methods for the 2,4-substitutedpyrimidinediamines described herein are also described in Examples 1-40,below. Those of skill in the art will also be able to readily adaptthese examples for the synthesis of additional 2,4-substitutedpyrimidinediamines as described herein.

A variety of exemplary synthetic routes that can be used to synthesizethe 2,4-pyrimidinediamine compounds of the invention are described inSchemes (I)-(VII), below. These methods may be routinely adapted tosynthesize the 2,4-substituted pyrimidinediamine compounds and prodrugsdescribed herein.

In one exemplary embodiment, the compounds can be synthesized fromsubstituted or unsubstituted uracils as illustrated in Scheme (I),below:

In Scheme (I), ring A, R¹, (R²)_(p), alk, (R³)_(q), R⁴, R⁵, X, Y and Zare as defined herein. According to Scheme (I), uracil A-1 isdihalogenated at the 2- and 4-positions using a standard halogenatingagent such as POCl₃ (or other standard halogenating agent) understandard conditions to yield 2,4-dichloropyrimidine A-2. Depending uponthe X substituent, in pyrimidinediamine A-2, the chloride at the C4position is more reactive towards nucleophiles than the chloride at theC2 position. This differential reactivity can be exploited to synthesize2,4-pyrimidinediamines A-7 by first reacting 2,4-dichloropyrimidine A-2with one equivalent of amine A-3, yielding4N-substituted-2-chloro-4-pyrimidineamine A-4, followed by amine A-5 toyield a 2,4-pyrimidinediamine derivative A-6, where N4 nitrogen can beselectively alkylated to give compounds of formula A-7.

Typically, the C4 halide is more reactive towards nucleophiles, asillustrated in the Scheme. However, as will be recognized by skilledartisans, the identity of the X substituent may alter this reactivity.For example, when X is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine A-4 and the corresponding2N-substituted-2-pyrimidineamine is obtained. The regioselectivity ofthe reaction can also be controlled by adjusting the solvent and othersynthetic conditions (such as temperature), as is well-known in the art.

The reactions depicted in Scheme (I) may proceed more quickly when thereaction mixtures are heated via microwave. When heating in thisfashion, the following conditions may be used: heat to 175° C. inethanol for 5-20 min. in a Smith Reactor (Personal Chemistry, Uppsala,Sweden) in a sealed tube (at 20 bar pressure).

The uracil 1 starting materials may be purchased from commercial sourcesor prepared using standard techniques of organic chemistry. Commerciallyavailable uracils that can be used as starting materials in Scheme (I)include, by way of example and not limitation, uracil (Aldrich#13,078-8; CAS Registry 66-22-8); 5-bromouracil (Aldrich #85,247-3; CASRegistry 51-20-7; 5-fluorouracil (Aldrich #85,847-1; CAS Registry51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry 696-07-1);5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5);5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS Registry 54-20-6).Additional 5-substituted uracils are available from GeneralIntermediates of Canada, Inc., Edmonton, CA and/or Interchim, Cedex,France, or may be prepared using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

Amines A-3 and A-5 may be purchased from commercial sources or,alternatively, may be synthesized utilizing standard techniques. Forexample, suitable amines may be synthesized from nitro precursors usingstandard chemistry. Specific exemplary reactions are provided in theExamples section. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

Skilled artisans will recognize that in some instances, amines A-3 andA-5 and/or substituent X on uracil A-1 may include functional groupsthat require protection during synthesis. The exact identity of anyprotecting group(s) used will depend upon the identity of the functionalgroup being protected, and will be apparent to those of skill in theart. Guidance for selecting appropriate protecting groups, as well assynthetic strategies for their attachment and removal, may be found, forexample, in Greene & Wuts, Protective Groups in Organic Synthesis, 3dEdition, John Wiley & Sons, Inc., New York (1999) and the referencescited therein (hereinafter “Greene & Wuts”).

Thus, protecting group refers to a group of atoms that, when attached toa reactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts, asmentioned above, and additionally, in Harrison et al., Compendium ofSynthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.Representative amino protecting groups include, but are not limited to,formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”),tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”),2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxylprotecting groups include, but are not limited to, those where thehydroxyl group is either acylated to form acetate and benzoate esters oralkylated to form benzyl and trityl ethers, as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPSgroups) and allyl ethers.

A specific embodiment of Scheme (I) utilizing 5-fluorouracil (Aldrich#32,937-1) as a starting material is illustrated in Scheme (Ia), below:

In Scheme (Ia), ring A, R¹, (R²)_(p), alk, (R³)_(q), R⁴, R⁵, Y and Z areas previously defined for Scheme (I). Asymmetric2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine A-11 may be obtainedby reacting 2,4-dichloro-5-fluoropyrimidine A-9 with one equivalent ofamine A-3 (to yield 2-chloro-N4-substituted-5-fluoro-4-pyrimidineamineA-10) followed by one or more equivalents of amine A-5.

In another exemplary embodiment, the 2,4-pyrimidinediamine compounds ofthe invention may be synthesized from substituted or unsubstitutedcytosines as illustrated in Schemes (IIa) and (IIb), below:

In Schemes (IIa) and (IIb), ring A, R¹, (R²)_(p), alk, (R³)_(q), R⁴, R⁵,X, Y and Z are as previously defined for Scheme (I) and PG represents aprotecting group. Referring to Scheme (IIa), the C4 exocyclic amine ofcytosine A-12 is first protected with a suitable protecting group PG toyield N4-protected cytosine A-13. For specific guidance regardingprotecting groups useful in this context, see Vorbrüggen andRuh-Pohlenz, 2001, Handbook of Nucleoside Synthesis, John Wiley & Sons,NY, pp. 1-631 (“Vorbrüggen”). Protected cytosine A-13 is halogenated atthe C2 position using a standard halogenation reagent under standardconditions to yield 2-chloro-4N-protected-4-pyrimidineamine A-14.Reaction with amine A-5 gives A-15, which on deprotection of the C4exocyclic amine, gives A-16. Reaction of A-16 with amine A-3 yields2,4-pyrimidinediamine derivative A-6.

Alternatively, referring to Scheme (IIb), cytosine A-12 may be reactedwith amine A-3 or protected amine A-19 to yield N4-substituted cytosineA-17 or A-20, respectively. These substituted cytosines may then behalogenated as previously described, deprotected (in the case ofN4-substituted cytosine A-20) and reacted with amine A-5 to yield a2,4-pyrimidinediamine A-11.

Commercially-available cytosines that may be used as starting materialsin Schemes (IIa) and (IIb) include, but are not limited to, cytosine(Aldrich #14,201-8; CAS Registry 71-30-7); N⁴-acetylcytosine (Aldrich#37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich#27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine.Other suitable cytosines useful as starting materials in Schemes (IIa)are available from General Intermediates of Canada, Inc., Edmonton, CAand/or Interchim, Cedex, France, or may be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention may be synthesized from substituted orunsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III),below:

In Scheme (III), ring A, R¹, (R²)_(p), alk, (R³)_(q), R⁴, R⁵, X, Y and Zare as previously defined for Scheme (I) and LG is a leaving group asdiscussed in more detail in connection with Scheme IV, infra. Referringto Scheme (III), 2-amino-4-pyrimidinol A-22 is reacted with arylatingagent A-23 to yield N2-substituted-4-pyrimidinol A-24, which is thenhalogenated as previously described to yieldN2-substituted-4-halo-2-pyrimidineamine A-25. Further reaction withamine A-3 affords a 2,4-pyrimidinediamine derivative A-6.

Suitable commercially-available 2-amino-4-pyrimidinols A-22 that can beused as starting materials in Scheme (III) are available from GeneralIntermediates of Canada, Inc., Edmonton, CA and/or Interchim, Cedex,France, or may be prepared using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

Alternatively, the 2,4-pyrimidinediamine compounds of the invention maybe prepared from substituted or unsubstituted 4-amino-2-pyrimidinols asillustrated in Scheme (IV), below:

In Scheme (IV), ring A, R¹, (R²)_(p), alk, (R³)_(q), R⁴, R⁵, X, Y and Zare as previously defined for Scheme (I). Referring to Scheme (IV), theC2-hydroxyl of 4-amino-2-pyrimidinol A-26 is more reactive towardsnucleophiles than the C4-amino such that reaction with amine A-5 yieldsN2-substituted-2,4-pyrimidinediamine A-27. Subsequent reaction withcompound A-28, which includes a suitable leaving group, or amine A-3yields a 2,4-pyrimidinediamine derivative A-6. Compound A-28 may includevirtually any leaving group that can be displaced by the C4-amino ofN2-substituted-2,4-pyrimidinediamine A-27. Suitable leaving groupsinclude, but are not limited to, halogens, methanesulfonyloxy (mesyloxy;“OMs”), trifluoromethanesulfonyloxy (“OTf”) and p-toluenesulfonyloxy(tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”) and m-nitro benzenesulfonyloxy (“nosylate”). Other suitable leaving groups will be apparentto those of skill in the art.

Substituted 4-amino-2-pyrimidinol starting materials may be obtainedcommercially or synthesized using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention can be prepared from2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines asillustrated in Scheme (V), below:

In Scheme (V), ring A, R¹, (R²)_(p), alk, (R³)_(q), R⁴, R⁵, X, Y and Zare as defined for Scheme (I) and leaving group is as defined for Scheme(IV). Referring to Scheme (V), 2-amino-4-chloropyrimidine A-29 isreacted with amine A-3 to yield 4N-substituted-2,4-pyrimidinediamineA-30 which, following reaction with compound A-23 or amine A-5, yields aN2,N4-2,4-pyrimidinediamine derivative A-6. Alternatively,2-chloro-4-amino-pyrimidine A-31 may be reacted with compound A-28 togive compound A-32 which on reaction with amine A-5 yields A-6.

A variety of pyrimidines A-29 and A-31 suitable for use as startingmaterials in Scheme (V) are commercially available from GeneralIntermediates of Canada, Inc., Edmonton, CA and/or Interchim, Cedex,France, or may be prepared using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

Alternatively, 4-chloro-2-pyrimidineamines A-29 may be prepared asillustrated in Scheme (Va):

In Scheme (Va), X is as previously defined for Scheme I. In Scheme (Va),dialdehyde A-33 is reacted with guanidine to yield 2-pyrimidineamineA-34. Reaction with a peracid such as m-chloroperbenzoic acid,trifluoroperacetic acid or urea hydrogen peroxide complex yields N-oxideA-35, which is then halogenated to give 4-chloro-2-pyrimidineamine A-29.The corresponding 4-halo-2-pyrimidineamines may be obtained by usingsuitable halogenation reagents.

In yet another exemplary embodiment, the 2,4-pyrimidinediamine compoundsof the invention can be prepared from substituted or unsubstituteduridines as illustrated in Scheme (VI), below:

In Scheme (VI), ring A, R¹, (R²)_(p), alk, (R³)_(q), R⁴, R⁵, X, Y and Zare as previously defined for Scheme (I) and PG represents a protectinggroup, as discussed in connection with Scheme (IIb). According to Scheme(VI), uridine A-36 has a C4 reactive center such that reaction withamine A-3 or protected amine A-19 yields N4-substituted cytidine A-37 orA-38, respectively. Acid-catalyzed deprotection of N4-substituted A-37or A-38 (when “PG” represents an acid-labile protecting group) yieldsN4-substituted cytosine A-39, which may be subsequently halogenated atthe C2-position and reacted with amine A-5 to yield a2,4-pyrimidinediamine derivative A-6.

Cytidines may also be used as starting materials in an analogous manner,as illustrated in Scheme (VII), below:

In Scheme (VII), ring A, R¹, (R²)_(p), alk, (R³)_(q), R⁴, R⁵, X, Y and Zare as previously defined in Scheme (I) and PG represents a protectinggroup as discussed above. Referring to Scheme (VII), like uridine A-36,cytidine A-40 has a C4 reactive center such that reaction with amine A-3or protected amine A-19 yields N4-substituted cytidine A-37 or A-38,respectively. These cytidines A-37 and A-38 are then treated aspreviously described for Scheme (VI) to yield a 2,4-pyrimidinediaminederivative A-6.

Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides,skilled artisans will appreciate that the corresponding 2′-deoxyribo and2′,3′-dideoxyribo nucleosides, as well as nucleosides including sugarsor sugar analogs other than ribose, would also work.

Numerous uridines and cytidines useful as starting materials in Schemes(VI) and (VII) are known in the art, and include, by way of example andnot limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem. Sources #ABCRF07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem. Sources Int'l2000; CAS Registry 957-75-5); 5-iodo-2′-deoxyuridine (Aldrich #1-775-6;CAS Registry 54-42-2); 5-fluorouridine (Aldrich #32,937-1; CAS Registry316-46-1); 5-iodouridine (Aldrich #85,259-7; CAS Registry 1024-99-3);5-(trifluoromethyl)uridine (Chem. Sources Int'l 2000; CAS Registry70-00-8); 5-trifluoromethyl-2′-deoxyuridine (Chem. Sources Int'l 2000;CAS Registry 70-00-8). Additional uridines and cytidines that can beused as starting materials in Schemes (VI) and (VII) are available fromGeneral Intermediates of Canada, Inc., Edmonton, CA and/or Interchim,Cedex, France, or may be prepared using standard techniques. Myriadtextbook references teaching suitable synthetic methods are providedinfra.

Although many of the synthetic schemes discussed above do not illustratethe use of protecting groups, skilled artisans will recognize that insome instances certain substituents, such as, for example, R² and/or R⁴,may include functional groups requiring protection. The exact identityof the protecting group used will depend upon, among other things, theidentity of the functional group being protected and the reactionconditions used in the particular synthetic scheme, and will be apparentto those of skill in the art. Guidance for selecting protecting groups,their attachment and removal suitable for a particular application canbe found, for example, in Greene & Wuts, supra.

Prodrugs as described herein may be prepared by routine modification ofthe above-described methods. Alternatively, such prodrugs may beprepared by reacting a suitably protected 2,4-pyrimidinediamine 6 with asuitable progroup. Conditions for carrying out such reactions and fordeprotecting the product to yield a prodrugs as described herein arewell-known.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Schemes (I)-(VII),are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II″); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV″); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidinediamine synthesis pp. 313-316; aminopyrimidinediamine synthesis pp. 315); Joule, J. A., Mills, K. and Smith,G. F., Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall,London, UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, —New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

Those of skill in the art will appreciate that the 2,4-substitutedpyrimidinediamine compounds described herein may include functionalgroups that can be masked with progroups to create prodrugs. Suchprodrugs are usually, but need not be, pharmacologically inactive untilconverted into their active drug form. Indeed, many of the2,4-substituted pyrimidinediamine compounds described in this inventioninclude promoieties that are hydrolyzable or otherwise cleavable underconditions of use. For example, ester groups commonly undergoacid-catalyzed hydrolysis to yield the parent carboxylic acid whenexposed to the acidic conditions of the stomach, or base-catalyzedhydrolysis when exposed to the basic conditions of the intestine orblood. Thus, when administered to a subject orally, 2,4-substitutedpyrimidinediamine compounds that include ester moieties may beconsidered prodrugs of their corresponding carboxylic acid, regardlessof whether the ester form is pharmacologically active.

The mechanism by which the progroup(s) metabolizes is not critical, andcan be caused by, for example, hydrolysis under the acidic conditions ofthe stomach, as described above, and/or by enzymes present in thedigestive tract and/or tissues or organs of the body. Indeed, theprogroup(s) can be selected to metabolize at a particular site withinthe body. For example, many esters are cleaved under the acidicconditions found in the stomach. Prodrugs designed to cleave chemicallyin the stomach to the active 2,4-substituted pyrimidinediamine canemploy progroups including such esters. Alternatively, the progroups maybe designed to metabolize in the presence of enzymes such as esterases,amidases, lipolases, phosphatases including ATPases and kinase etc.Progroups including linkages capable of metabolizing in vivo arewell-known, and include, by way of example and not limitation, ethers,thioethers, silylethers, silylthioethers, esters, thioesters,carbonates, thiocarbonates, carbamates, thiocarbamates, ureas,thioureas, carboxamides, etc. In some instances, a “precursor” groupthat is oxidized by oxidative enzymes such as, for example, cytochromeP450 of the liver, to a metabolizable group, can be selected.

In the prodrugs, any available functional moiety may be masked with aprogroup to yield a prodrug. Functional groups within the2,4-substituted pyrimidinediamine compounds that may be masked withprogroups for inclusion in a promoiety include, but are not limited to,amines (primary and secondary), hydroxyls, sulfanyls (thiols),carboxyls, etc. Myriad progroups suitable for masking such functionalgroups to yield promoieties that are cleavable under the desiredconditions of use are known in the art. All of these progroups, alone orin combinations, may be included in the prodrugs.

In some embodiments of the 2,4-substituted pyrimidinediamine compoundsand methods of using the compounds, the progroup(s) can be attached toany available primary or secondary amine, including, for example, the N2nitrogen atom of the 2,4-pyrimidinediamine moiety, the N4 nitrogen atomof the 2,4-pyrimidinediamine moiety, and/or a primary or secondarynitrogen atom included in a substituent on the 2,4-pyrimidinediaminecompound.

In particular embodiments of the 2,4-substituted pyrimidinediaminecompounds and methods of using the compounds, the prodrugs describedherein are 2,4-substituted pyrimidinediamine compounds that aresubstituted at the N4 nitrogen of the 2,4-pyrimidinediamine moiety witha substituted or unsubstituted nitrogen-containing bicyclic ring thatincludes at least one progroup at one or more of: the nitrogen atom(s)of the bicyclic ring, the N2 nitrogen of the 2,4-pyrimidinediaminemoiety and/or the N4 nitrogen of the 2,4-pyrimidinediamine moiety.

As noted above, the identity of the progroup is not critical, providedthat it can be metabolized under the desired conditions of use, forexample under the acidic conditions found in the stomach and/or byenzymes found in vivo, to yield a the biologically active group, e.g.,the 2,4-substituted pyrimidinediamines as described herein. Thus,skilled artisans will appreciate that the progroup can comprisevirtually any known or later-discovered hydroxyl, amine or thiolprotecting group. Non-limiting examples of suitable protecting groupscan be found, for example, in Protective Groups in Organic Synthesis,Greene & Wuts, 2nd Ed., John Wiley & Sons, —New York, 1991 (especiallypages 10-142 (alcohols, 277-308 (thiols) and 309-405 (amines) thedisclosure of which is incorporated herein by reference).

Additionally, the identity of the progroup(s) can also be selected so asto impart the prodrug with desirable characteristics. For example,lipophilic groups can be used to decrease water solubility andhydrophilic groups can be used to increase water solubility. In thisway, prodrugs specifically tailored for selected modes of administrationcan be obtained. The progroup can also be designed to impart the prodrugwith other properties, such as, for example, improved passive intestinalabsorption, improved transport-mediated intestinal absorption,protection against fast metabolism (slow-release prodrugs),tissue-selective delivery, passive enrichment in target tissues,targeting-specific transporters, etc. Groups capable of impartingprodrugs with these characteristics are well-known, and are described,for example, in Ettmayer et al., 2004, J. Med. Chem. 47(10):2393-2404,the disclosure of which is incorporated by reference. All of the variousgroups described in these references can be utilized in the prodrugsdescribed herein.

As noted above, progroup(s) may also be selected to increase the watersolubility of the prodrug as compared to the active drug. Thus theprogroup(s) may include or may be a group(s) suitable for imparting drugmolecules with improved water solubility. Such groups are well-known,and include, by way of example and not limitation, hydrophilic groupssuch as alkyl, aryl, arylalkyl, or cycloheteroalkyl groups substitutedwith one or more of an amine, alcohol, a carboxylic acid, a phosphorousacid, a sulfoxide, a sugar, an amino acid, a thiol, a polyol, an ether,a thioether and a quaternary amine salt.

The suitability of any particular progroup for a desired mode ofadministration can be confirmed in biochemical assays. For example, if aprodrug is to be administered by injection into a particular tissue ororgan, and the identities of the various enzyme(s) expressed in thetissue or organ are known, the particular prodrug can be tested formetabolism in biochemical assays with the isolated enzyme(s).Alternatively, the particular prodrug can be tested for metabolism tothe active 2,4-substituted pyrimidinediamine compound with tissue and/ororgan extracts. Using tissue and/or organ extracts can be of particularconvenience when the identity(ies) of the enzymes expressed in thetarget tissues or organs are unknown, or in instances when the isolatedenzymes are not conveniently available. Skilled artisans will be able toreadily select progroups having metabolic properties (such as kinetics)suitable for particular applications using such in vitro tests. Ofcourse, specific prodrugs could also be tested for suitable metabolismin in vivo animal models.

Numerous references teach the use and synthesis of prodrugs, including,for example, Ettmayer et al., ibid and Bungaard et al., (1989) J. Med.Chem. 32(12): 2503-2507. Additionally, the preparation and use ofprodrugs of 2,4-pyrimidinediamines is specifically taught in U.S.Provisional Patent Application 60/654,620, filed Feb. 18, 2005, entitled“Pyrimidinediamine Prodrugs and their Uses,” the disclosure of which ishereby incorporated by reference in its entirety.

IV. Examples

The invention is further understood by reference to the followingexamples, which are intended to be purely exemplary of the invention.The present invention is not limited in scope by the exemplifiedembodiments, which are intended as illustrations of single aspects ofthe invention only. Any methods that are functionally equivalent arewithin the scope of the invention. Various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications fall within the scope of the appended claims.

In the examples below as well as throughout the application, thefollowing abbreviations have the following meanings. If not defined, theterms have their generally accepted meanings.

-   -   TFA=Trifluoroacetic acid    -   MeOH=Methanol    -   EtOH=Ethanol    -   mL=Milliliter    -   mmol=Millimole    -   DCM or CH₂Cl₂=methylene chloride    -   M=Molar    -   DMSO=dimethylsulfoxie    -   s=Singlet    -   d=Doublet    -   t=Triplet    -   q=Quartet    -   m=Multiplet    -   dd=double doublet    -   br=Broad    -   MS=mass spectrum    -   LC=liquid chromatography    -   Pd/C=palladium over carbon    -   HCl=hydrochloric acid    -   uL=Microliter    -   h=Hour    -   K₂CO₃=potassium carbonate    -   g=Gram    -   d=Days    -   RT or rt=room temperature    -   mg=Milligram    -   aq=Aqueous    -   THF=tetrahydrofuran    -   NaOH=sodium hydroxide    -   EtOAc=ethyl acetate    -   NH₃=Ammonia    -   DMF=dimethylformamide    -   DMAP=dimethylaminopyridine    -   TEA=Triethylamine    -   tBuOH=tert-butanol    -   Cs₂CO₃=cesium carbonate    -   iPrOH=Isopropanol    -   H₂O₂=hydrogen peroxide    -   HPLC=high pressure liquid chromatography    -   Na₂SO₄=sodium sulfate    -   psi=pound per square inch    -   NH₄Cl=ammonium chloride    -   Cu₂O=cuprous oxide    -   N=Normal    -   NH₄OH=ammonium hydroxide    -   POCl₃=phosphorous oxychloride    -   H₂O=Water    -   NaOMe=sodium methoxide    -   NaHCO₃=sodium bicarbonate    -   μM=Micromolar

Example 1

5-methyl-3-(4-nitrophenoxymethyl)isoxazole (3, X═H)

To a dry reaction flask equipped with a reflux condenser, a magneticstirring bar and a rubber septum with a N₂ inlet was placed4-nitrophenol (2, X═H) (1.57 g, 11.36 mmol), anhydrous K₂CO₃ (1.58 g, 12mmol) and tetrabutylammonium iodide (200 mg) in dry acetone (100 mL).The reaction mixture was stirred at room temperature for 30 minutes. Tothis heterogeneous mixture was added 3-(bromomethyl)-5-methylisoxazole(2.0 g, 11.36 mmol) at room temperature and then the reaction mixturewas refluxed for over night. After cooling it to room temperature, thereaction mixture was filtered, washed with acetone (50 mL) and thecombined filtrates were concentrated under reduced pressure. Theresulting solid was purified by silica gel column, eluted with hexanesthen polarity was increased gradually up to 40% EtOAc in hexanes to give2.59 g (97%) of the desired 5-methyl-3-(4-nitrophenoxymethyl)isoxazole(3, X═H). ¹H NMR (CDCl₃): δ 8.19 (d, 2H, J=9.3 Hz), 7.04 (d, 2H, J=9.6Hz), 6.18 (s, 1H), 5.20 (s, 2H), 2.44 (s, 3H); LCMS (m/z): 235 (MH⁺).

3-(4-Aminophenoxymethyl)-5-methylisoxazole (4, X═H)

The 5-methyl-3-(4-nitrophenoxymethyl)isoxazole (3, X═H) (2.59 g, 11.07mmol) was dissolved in MeOH:CH₂Cl₂ (1:1, 600 mL). An aqueous solution of(77 mL) sodium hydrosulfite (11.93 g, 68.5 mmol) and K₂CO₃ (9.55 g, 69mmol) was added dropwise under nitrogen for 30 min. The reaction wasallowed to stir at room temperature for 2 h, and the organic solventswere removed under reduced pressure, diluted with water (200 mL),extracted with CH₂Cl₂ (3×300 mL), dried over anhydrous Na₂SO₄ andsolvent was removed under reduced pressure. The resulting product wasfinally dried under high vacuum to afford 1.03 g (46%) of the5-methyl-3-(4-aminophenoxymethyl)isoxazole (4, X═H). ¹H NMR (CDCl₃): δ6.78 (d, 2H, J=8.7 Hz), 6.61 (d, 2H, J=8.4 Hz), 6.07 (s, 1H), 5.01 (s,2H), 3.44 (s, 2H), 2.40 (s, 3H); LCMS (m/z): 205 (MH⁺).

The following compounds were made in a similar fashion to the example 1.

5-Methyl-3-(2-methyl-4-nitrophenoxymethyl)isoxazole (3, X═CH₃)

¹H NMR (CDCl₃): δ 8.08 (d, 1H, J=2.7 Hz), 8.04 (s, 1H), 6.96 (d, 1H,J=8.7 Hz), 6.08 (s, 1H), 5.21 (s, 2H), 2.44 (s, 3H), 2.30 (s, 3H); LCMS(m/z): 249 (MH⁺).

3-(2-Fluoro-4-nitrophenoxymethyl)-5-methylisoxazole (3, X═F)

LCMS: purity: 98%; MS (m/e): 254 (MH+).

3-(4-Amino-2-methylphenoxymethyl)-5-methylisoxazole (4, X═CH₃)

¹H NMR (CDCl₃): δ 6.70 (d, 1H, J=8.7 Hz), 6.52 (d, 1H, J=2.7 Hz), 6.45(dd, 1H, J=2.7 and 8.4 Hz), 6.07 (s, 1H), 5.00 (s, 2H), 3.39 (s, 2H),2.41 (s, 3H), 2.17 (s, 3H); LCMS (m/z): 219 (MH⁺).

3-(4-Amino-2-fluorophenoxymethyl)-5-methylisoxazole (4, X═F)

LCMS: purity: 89%; MS: 224 (MH+).

Example 2

4-methyl-3-methoxycarbonylmethyleneoxynitrobenzene (6)

A reaction flask equipped with a reflux condenser, a magnetic stirrerbar and nitrogen inlet was charged with 2-methyl-5-nitrophenol (5) (5.0g, 32.6 mmol), K₂CO₃ (4.51 g, 32.6 mmol) and acetone (35 mL). To thisheterogeneous mixture was added methyl bromoacetate (2.7 mL, 29.34 mmol)at room temperature and then refluxed for 24 hours. Upon cooling, thereaction mixture was poured over ice water (200 mL). The solid crashedout, was filtered, washed with water (3×50 mL) and dried under a highvacuum to obtain 7.0 g of4-methyl-3-methoxycarbonylmethyleneoxynitrobenzene (6). LCMS: purity:95%; MS (m/z): 226(MH⁺).

4-methyl-3-methylaminocarbonylmethyleneoxynitrobenzene (7)

A mixture of 4-methyl-3-methoxycarbonylmethyleneoxynitrobenzene (6) (7.0g, 31 mmol), methylamine hydrochloride (20.93 g, 310 mmol) anddiisopropylethyl amine (DIPEA) (28 mL, 155 mmol) in methanol (100 mL)was stirred in a pressure tube at 90° C. for 6 hours. The reaction wascooled to room temperature, and diluted with water (1 Liter). The solidobtained was filtered, washed with water (3×150 mL) and dried to obtain6 g of 4-methyl-3-methylaminocarbonylmethyleneoxynitrobenzene (7). LCMS:purity: 98%; MS (m/z): 225(MH⁺).4-methyl-3-methylaminocarbonylmethyleneoxyaniline (8)

The hydrogenation of4-methyl-3-methylaminocarbonylmethyleneoxynitrobenzene (7) (1.0 g) wasconducted using 10% Pd/C (100 mg) in methanol (50 mL) at 40 PSI for 4hours to give 0.8 g of 4-methyl-3-methylaminocarbonylmethyleneoxyaniline(8) after filtration of catalyst and removal of solvent under reducedpressure. LCMS: purity: 93%; MS (m/e): 195(MH+).

4-methyl-3-(2-methylamino)ethyloxynitrobenzene (9)

A dry reaction flask equipped with a reflux condenser, a magneticstirring bar and a nitrogen inlet was charged with4-methyl-3-methylaminocarbonylmethyleneoxynitrobenzene (7) (0.5 g, 2.23mmol) and THF (5 mL). The resulting suspension was cooled to 0° C. andto it was added borane methylsulfide complex (3.3 mL, 2M) over a periodof 5 minutes and then the reaction mixture was brought to roomtemperature and then refluxed for 2 hours. After removal of solventunder vacuum, the addition of methanol was performed carefully (CAUTION!methanol reacts violently with the residual/unreacted boranemethylsulfide complex). The resulting methanolic solution was stirred atroom temperature for 30 minutes and methanol and volatiles were removedunder reduced pressure. This process was repeated twice. The methanolicsolution was then treated with 4N HCl (in dioxane (4.4 mmol, 1.1 mL) andthen heated at 60° C. for 2.5 hours. The solvent was removed under areduced pressure. The mixture was treated with 2M NH₃/methanol (8.8mmol, 4.4 mL) and the solvent was then removed under a reduced pressure.The residual product was chromatographed (silica gel, eluted withhexanes then 20% ethyl acetate in hexanes) to obtain 0.350 g of4-methyl-3-(2-methylamino)ethyloxynitrobenzene (9). LCMS: purity: 92%;MS (m/z): 211(MH⁺).

4-methyl-3-(2-methylamino)ethyloxyaniline (10)

The hydrogenation of 4-methyl-3-(2-methylamino)ethyloxynitrobenzene (9)(0.5 g) was conducted using 10% Pd/C (50 mg) in methanol (20 mL) at 40psi for 4 hours to give 0.350 g of4-methyl-3-(2-methylamino)ethyloxyaniline (10). LCMS: purity: 90%; MS(m/z): 181(MH⁺).

Example 3

Acetamide oxime.triethylamine hydrochloride salt (11)

Hydroxylamine hydrochloride (3.38 g, 48.64 mmol) and triethyl amine(NEt₃) (5.1 g, 7.0 mL, 50.4 mmol) were added to a stirred solution ofacetonitrile (2.0 g, 2.54 mL, 48.72 mmol) in MeOH (10 mL) at roomtemperature and then refluxed for 3 days. The solvent was removed underreduced pressure and then dried under high vacuum to provide the desiredacetamide oxime triethylamine hydrochloride salt (11) as a whitecrystalline solid.

3-Methyl-5-(4-nitrophenoxymethyl)-1,2,4-oxadiazole (13a)

A mixture of 4-nitrophenoxyacetic acid (12) (2.25 g, 11.4 mmol),acetamide oxime triethylamine hydrochloride salt (11, 5.85 g, 27.62mmol), EDCl.HCl (4.37 g, 22.79 mmol) and diisopropylethylamine (7.42 g,10 mL, 57.40 mmol) in anhydrous tetrahydrofuran (THF) (250 mL) wasrefluxed for 18 hours. The heterogeneous brown reaction mixture was thenquenched with water and extracted with EtOAc (3×300 mL). The combinedorganic layers were washed successively with aqueous sodium bicarbonate(NaHCO₃) and brine. The resulting organic phase was dried over anhydrousNa₂SO₄ and solvent was removed by using rotary evaporator. The resultingresidue was purified by silica gel column chromatography to yield 1.62 g(60%) of the desired product,3-methyl-5-(4-nitrophenoxymethyl)-1,2,4-oxadiazole (13a) as a whitesolid. ¹H NMR (CDCl₃, 300 MHz): δ 8.24 (d, 2H, J=8.8 Hz), 7.08 (d, 2H,J=8.8 Hz), 5.36 (s, 2H), 2.44 (s, 3H); LCMS (m/z): 236 (MH⁺).

5-(4-Aminophenoxymethyl)-3-methyl-1,2,4-oxadiazole (14a)

Prepared by following the procedure described in Example 1. ¹H NMR(CDCl₃): δ 6.82 (d, 2H, J=8.8 Hz), 6.63 (d, 2H, J=8.8 Hz), 5.15 (s, 2H),3.38 (br s, 2H), 2.41 (s, 3H); LCMS (m/z): 206 (MH⁺).

The following compounds were made in a similar fashion to the example 3.

3-Methyl-5-(3-nitrophenoxymethyl)-1,2,4-oxadiazole (13b)

¹H NMR (CDCl₃, 300 MHz): δ 7.92 (dd, 1H, J=0.9 and 1.9 Hz), 7.89 (dd,1H, J=0.9 and 2.1 Hz), 7.83 (t, 1H, J=2.1 Hz), 7.33 (m, 1H), 5.34 (s,2H), 2.44 (s, 3H); LCMS (m/z): 236 (MH⁺).

5-(3-Aminophenoxymethyl)-3-methyl-1,2,4-oxadiazole (14b)

¹H NMR (CDCl₃): δ 7.05 (t, 1H, J=8.4 Hz), 6.36-6.29 (m, 3H), 5.19 (s,2H), 3.69 (br s, 2H), 2.42 (s, 3H); LCMS (m/z): 206 (MH⁺).

3-Methyl-5-(4-nitrophenethyl)-1,2,4-oxadiazole

¹H NMR (DMSO-d₆): δ 8.15-8.12 (d, J=9.0 Hz, 2H), 7.56-7.53 (d, J=9.0 Hz,2H), 3.28-3.26 (m, 2H), 3.22-3.20 (m, 2H), and 2.28 (s, 3H).

4-[2-(3-Methyl-1,2,4-oxadiazol-5-yl)ethyl]aniline

LCMS: purity: 91%; MS (m/e): 204 (M+).

Example 4

ethyl-1-benzyl-3-methylpyrazole-5-carboxylate (16)

An acetonitrile (8.0 mL) mixture ofethyl-3-methyl-1H-pyrazole-5-carboxylate (15) (0.50 g. 3.2 mmol), benzylbromide (0.48 mL, 4.0 mmol), and K₂CO₃ (0.90 g, 6.5 mmol) was stirred atroom temperature overnight. The reaction mixture was diluted with water(50 mL) and extracted with dichloromethane. The combined organic layerswere washed with brine and dried over anhydrous magnesium sulfate. Afterremoval of solvent under reduced pressure, the residue was purified byflash column chromatography [silica gel, eluting with mixtures of ethylacetate and hexanes (0% ramped to 15% EtOAc/hexanes)] to yield 0.30 g ofethyl-1-benzyl-3-methylpyrazole-5-carboxylate (16). ¹H NMR (CDCl₃): δ7.30-7.22 (m, 5H), 6.65 (s, 1H), 5.71 (s, 2H), 4.28 (q, J=7.2 Hz, 2H),2.32 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); LCMS: purity: 99%; MS (m/z):345(MH⁺).

4-[(1-benzyl-3-methylpyrazol-5-yl)methyleneoxy]nitrobenzene (18)

To a suspension of ethyl-1-benzyl-3-methylpyrazole-5-carboxylate (16)(0.30 g, 1.2 mmol) in anhydrous toluene (6.0 mL) at 0° C. was added asolution of diisobutyl aluminum hydride (DIBAL-H) (3.4 mL, 3.4 mmol, 1Min toluene) drop-wise. The reaction mixture was then stirred at roomtemperature for 1 hour. The reaction mixture was diluted with ether (50mL) followed by addition of Rochelle's salt (50 mL, 0.5 M) and thenstirred vigorously at room temperature for 2 hours. The aqueous layerwas separated and extracted further with ether. The combined organiclayers were washed with brine and dried over anhydrous magnesiumsulfate. The crude product 17 (0.23 g) obtained after concentration wasused without further purification.

The product 17 (0.23 g, 1.0 mmol) was suspended in anhydrousdichloromethane (8.0 mL), and to this solution were added triethylamine(0.29 mL, 2.1 mmol), 4-dimethylaminopyridine (5 mg, 0.04 mmol) andp-toluenesulfonylchloride (0.21 g, 1.1 mmol). The reaction mixture wasthen stirred at room temperature for 3.5 hours and then diluted withdichloromethane (10 mL) and saturated NH₄Cl (15 mL). The organic layerwas separated, dried over anhydrous magnesium sulfate, and concentratedunder vacuum. The crude product was passed through a pad of silica geleluting with mixtures of ethyl acetate and hexanes (0% ramped to 5%EtOAc/hexanes) to give the tosylate as yellow oil (0.135 g). Thetosylate (0.135 g, 0.379 mmol) was combined with 4-nitrophenol (66 mg,0.47 mmol) and K₂CO₃ (0.10 g, 0.76 mmol) in anhydrous dimethylformamide(DMF) (2.0 mL). The mixture was then stirred at 65° C. overnight. Thereaction mixture was cooled to room temperature and poured over water(20 mL) and the resulting solid of the desired product,4-[(1-benzyl-3-methylpyrazol-5-yl)methyleneoxy]nitrobenzene (18) wasisolated by suction filtration as a white solid (0.155 g). ¹H NMR(CDCl₃): δ 8.16 (d, J=9.0 Hz, 2H), 7.29-7.25 (m, 3H), 7.11-7.06 (m, 2H),6.83 (d, J=9.0 Hz, 2H), 6.20 (s, 1H), 5.39 (s, 2H), 4.96 (s, 2H), and2.34 (s, 3H).

4-[(1-benzyl-3-methylpyrazol-5-yl)methyleneoxy]aniline (19, Y=Benzyl)

LCMS: purity: 85%; MS (m/e): 294 (MH+).

Example 5

4-Aminocarbonylmethyleneoxynitrobenzene (20)

4-Nitrophenol (10 g), bromoacetamide (10 g) and K₂CO₃ (15 g) weresuspended in acetone (30 mL). The yellow solution was stirred at roomtemperature for 3 days. The reaction mixture was diluted with distilledwater and acetone was removed under reduced pressure. The light-yellowprecipitate was collected by filtration, washed with water (3×100 mL)and dried to give 4-aminocarbonylmethyleneoxynitrobenzene (20) (11.5 g)as beige solid.

4-(aminocarbonylmethyleneoxy)aniline (21)

4-Aminocarbonylmethyleneoxynitrobenzene (20) (5 g) was dissolved inmethanol (50 mL) and to it was added 10% Pd—C (500 mg). The reactionmixture was reacted under hydrogen atmosphere (˜40 psi) for 1 h. Thecatalyst was filtered off through a pad of celite. The filtrate wasconcentrated under reduced pressure to give4-(aminocarbonylmethoxy)aniline (21) as a white solid.

Example 6

4-Cyanomethyleneoxynitrobenzene (22)

4-Nitrophenol (10 g), bromoacetonitrile (6 mL) and K₂CO₃ (15 g) weresuspended in acetone (100 mL). The yellow solution was stirred at roomtemperature overnight. The reaction mixture was diluted with water (100mL) and acetone was removed under reduced pressure. The light-yellowprecipitate was collected by filtration, washed with distilled water(3×100 mL) and dried to give 4-cyanomethyleneoxynitrobenzene (22).

4-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxynitrobenzene (23)

4-Cyanomethyleneoxynitrobenzene (22) (8 g) was dissolved in methanol (50mL) and to the solution was added hydroxyamine HCl (3.4 g) andtriethylamine (9.4 mL). The reaction mixture was refluxed for 4 days andthe solvent was removed under reduced pressure. The residue wasredissolved in THF (50 mL). To the solution was added acetyl chloride(AcCl) (23 mL) and triethylamine (50 mL). The reaction mixture wasstirred at room temperature overnight, then was added water (30 mL) andNaOH (18 g). The reaction solution was refluxed overnight and dilutedwith water (200 mL). The aqueous solution was extracted with EtOAc(2×150 mL). After separation, the combined EtOAc layers were dried overanhydrous sodium sulfate and then solvent was removed under a reducedpressure. The resulting residue was purified by flash columnchromatography) (EtOAc/hexanes=½ (v/v), 1/1, EtOAc) and recrystallizedfrom EtOAc and hexanes to give4-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxynitrobenzene (23).

4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxyaniline (24)

4-(5-Methyl-1,2,4-oxadiazol-3-yl)methyleneoxynitrobenzene (1 g) wasdissolved in THF (40 mL) and water (40 mL). Sodium bisulfite (3.8 g),sodium bicarbonate (1.4 g), and K₂CO₃ (1.8 g) were added to thesolution. The solution was stirred at room temperature for 30 minutesand diluted with water (80 mL). The aqueous solution was extracted withEtOAc (2×100 mL). The organic layers were then combined, dried overanhydrous sodium sulfate and solvent was removed under reduced pressureto give 4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxyaniline (24).

Example 7

3-chlorosulfonyl-4-fluoro-5-methylnitrobenzene (26)

A dry reaction flask equipped with a stirring bar, a reflux condenserand nitrogen inlet was charged with 4-fluoro-3-methylnitrobenzene (25)(3.10 g, 20 mmol). To this at 0° C., was added dropwise chlorosulfonicacid (5.29 mL, 80 mmol) over a period of 15 minutes. After bringing thehomogeneous solution to room temperature, it was stirred at 110° C. for24 hours. The resulting slurry was then poured over ice water (100 gm),extracted with diethyl ether (3×75 mL), and the organic phase washedwith water (75 mL), then dried over anhydrous sodium sulfate. Thesolvent was then removed under reduced pressure to afford thecorresponding sulfonyl chloride derivative (26), which was used furtherwithout purification.

3-aminosulfonyl-4-fluoro-5-methylnitrobenzene (27)

The resulting oily residue of compound 26 was taken up in ethyl acetate(100 mL) and stirred with ammonium hydroxide (100 mL, 30% aqueoussolution) overnight at room temperature. After the ethyl acetate layerwas separated, the aqueous layer was extracted with ethyl acetate (2×50mL). The organic layers were combined, dried over anhydrous sodiumsulfate and the solvent was removed under vacuum. The dark oily residuewas chromatographed (silica gel, hexanes then 10%, 20%, up to 50% ethylacetate in hexanes to afford3-aminosulfonyl-4-fluoro-5-methylnitrobenzene (27). LCMS: purity: 89%;MS (m/z): 235 (MH⁺).

Synthesis of 3-Aminosulfonyl-4-fluoro-5-methylaniline (28)

To a heterogeneous solution of3-aminosulfonyl-4-fluoro-5-methylnitrobenzene (27) (0.5 g, 2 mmol) in ofethanol:water (50 mL, each) were added iron powder (1.08 g, 20 mmol),and ammonium chloride (1.08 g, 20 mmol) at room temperature. Theresulting heterogeneous mixture was then stirred at 60° C. for 2 hours,filtered through celite (when hot), washed with ethanol (2×50 mL) andthen the solvent was removed under reduced pressure. The residue upondilution with water was extracted with ethyl acetate (3×50 mL), and theorganic phase was dried over anhydrous sodium sulfate and concentratedunder a reduced pressure to obtain3-aminosulfonyl-4-fluoro-5-methylaniline (28). LCMS: purity: 85%; MS(m/z): 205 (MH⁺).

3-Aminosulfonyl-4-fluoroaniline

To a solution of 3-aminosulfonyl-4-fluoronitrobenzene (360 mg, 1.62mmol) in dichloromethane (6 mL) and methanol (3 mL) was added 10% Pd/C(36 mg) and shaken under a hydrogen atmosphere at 50 psi for 15 minutes.The mixture was filtered through Celite and the cake was washed withmethanol (5 mL). The combined organic solvent was concentrated underreduced pressure to give crude product, which was further purified byflash column chromatography (ethyl acetate: hexanes 1:1) to give 240 mgof 5-amino-2-fluorobenzensulfonamide as a light yellow solid. ¹H NMR(DMSO-d₆): δ 7.38 (s, 2H), 7.03-6.94 (m, 2H), 6.70-6.66 (m, 1H), 5.33(s, 1H).

The following compounds were made in a similar fashion to the example 7.

3-Aminosulfonyl-4-methylnitrobenzene

LCMS: purity: 95%; MS (m/e): 217 (MH+).

3-Aminosulfonyl-4-fluoronitrobenzene

¹H NMR (DMSO-d₆): δ 8.53-8.50 (m, 2H), 8.04 (s, 2H), and 7.77-7.70 (m,1H).

3-Aminosulfonyl-4-chloro-5-methylnitrobenzene

LCMS: purity: 86%; MS (m/e): 252 (MH+).

3-Aminosulfonyl-5-chloro-4-methylnitrobenzene

LCMS: purity: 96%; MS (m/e): 252 (MH+).

3-Aminosulfonyl-4-methylaniline

LCMS: purity: 87%; MS (m/e): 187 (MH+).

3-Aminosulfonyl-4-chloro-5-methylaniline

LCMS: purity: 98%; MS (m/e): 222 (MH+).

3-Aminosulfonyl-5-chloro-4-methylaniline

LCMS: purity: 97%; MS (m/e): 222 (MH+).

3-Aminosulfonyl-4-chloroaniline

LCMS: purity: 98%; MS (m/e): 239 (MH+).

Example 8

6-Bromo-3-hydroxy-2-nitropyridine (30)

A dry reaction flask equipped with a magnetic stirring bar and nitrogeninlet was charged with 3-hydroxy-2-nitropyridine (29) (28 g, 200 mmol)and methanol (560 mL). To this homogeneous mixture at room temperaturewas added sodium methoxide (25 wt %, in methanol; 181 mmol, 46.15 mL)over a period of 30 minutes. The resulting solution was cooled to 0° C.and to it was added bromine (10.31 mL, 200 mmol) over a period of 15minutes. The reaction mixture was then stirred at 0° C. for anadditional 30 minutes. The reaction was quenched with glacial aceticacid (3.5 mL), then the reaction mixture was concentrated to dryness,and then diluted with water (1 Liter). The solid obtained was filteredand washed with water (2×100 mL) to obtain 60:40 mixture of6-bromo-3-hydroxy-2-nitropyridine (30):4,6-dibromo-3-hydroxy-2-nitropyridine (31). LCMS: MS (m/z): 219 (MH⁺)and 297 (MH⁺), respectively. 60:40 mixture of6-bromo-3-hydroxy-2-nitropyridine (30):4,6-dibromo-3-hydroxy-2-nitropyridine (31) was used as such for the nextexperiment.

6-Bromo-3-methoxy-2-nitropyridine (32)

To a heterogeneous 60:40 mixture of 6-bromo-3-hydroxy-2-nitropyridine(30): 4,6-dibromo-3-hydroxy-2-nitropyridine (31) (2.18 g, 10 mmol),K₂CO₃ (2.08 g, 15 mmol) in N,N-dimethylformamide (DMF) (20 mL) was addeddimethyl sulfate (DMS) (1.13 mL, 12 mmol) and the resulting mixture wasstirred at 60° C. for 24 hours. The reaction mixture was poured overice-water (100 mL), extracted with ethyl acetate (3×50 mL), and theorganic phase was dried over anhydrous sodium sulfate. The solvent wasthen removed under reduced pressure to afford6-bromo-3-methoxy-2-nitropyridine (32). LCMS: purity: 92%; MS (m/z): 233(MH⁺).

2-Amino-6-bromo-3-methoxypyridine (33)

To a heterogeneous solution of 6-bromo-3-methoxy-2-nitropyridine (32)(2.32 g, 10 mmol) in of ethanol:water (40 mL, each) were added ironpowder (2.8 g, 50 mmol), followed by ammonium chloride (2.64 g, 50 mmol)at room temperature. The resulting heterogeneous mixture was thenstirred at 70-75° C. for 15 minutes, filtered through celite (when hot),washed with ethanol (2×50 mL) and solvent was then removed under reducedpressure. The residue upon dilution with water afforded a solid, whichwas isolated by filtration to give 2-amino-6-bromo-3-methoxypyridine(33). LCMS: purity: 95%, MS (m/z): 203 (MH⁺).

6-Bromo-2-(tert-butylcarbonyl)amino-3-methoxypyridine (34)

A dry reaction flask equipped with a nitrogen inlet and magneticstirring bar was charged with 2-amino-6-bromo-3-methoxypyridine (33)(0.170 g, 0.84 mmol), pyridine (0.126 mL, 1.26 mmol) and CH₂Cl₂ (5 mL).To this at 0° C. was added pivaloyl chloride (0.113 mL, 0.92 mmol) andthen the reaction mixture was stirred at room temperature overnight. Thereaction was then quenched with water (25 mL), extracted with CH₂Cl₂(2×25 mL), dried over anhydrous sodium sulfate and solvent was removedunder reduced pressure to afford6-bromo-2-(tert-butylcarbonyl)amino-3-methoxypyridine (34). LCMS:purity: 80%; MS (m/z): 287 (MH⁺).

6-Amino-2-(tert-butylcarbonyl)amino-3-methoxypyridine (35)

A pressure tube was charged with6-bromo-2-(tert-butylcarbonyl)amino-3-methoxypyridine (34) (0.287 g),ethylene glycol (3 mL) and Cu₂O (0.028 g) and cooled to −78° C. To thismixture, 1 mL of liquid ammonia was collected (at −78° C.), the pressuretube was sealed and then stirred at room temperature for 24 hours. Thereaction mixture was again cooled to −78° C., the seal was removed andthe reaction mixture diluted with water (10 mL). The aqueous solutionwas extracted with ethyl acetate (3×50 mL), dried over anhydrous sodiumsulfate and solvent was removed under a reduced pressure. The resultingresidue was chromatographed (silica gel, CH₂Cl₂ then 1% 2N NH₃/MeOH inCH₂Cl₂ to obtain 6-amino-2-(tert-butylcarbonyl)amino-3-methoxypyridine(35). LCMS: purity: 94%; MS (m/z): 224 (MH⁺).

Example 9

3-(4-Nitrophenyl)propionitrile (38)

To a mixture of 4-nitrobenzyl alcohol (37) (1 g, 6.53 mmol) and(cyanomethyl)trimethylphosphonium iodide (36) (4 g, 16.32 mmol) wereadded propionitrile (32 mL) and diisopropylethylamine (2.5 g, 19.58mmol) at room temperature. The mixture was heated at ˜100° C. for 24hours. The reaction was quenched with water (1 mL), followed by additionof concentrated HCl (5 mL). The resulting reaction mixture was extractedwith ethyl acetate (3×100 mL), washed with brine, dried over anhydroussodium sulfate, and then concentrated under reduced pressure to give adark brown solid. The crude solid product was purified by flash columnchromatography (silica gel, ethyl acetate: hexanes 1:1) to give 740 mgof 3-(4-nitrophenyl)propionitrile (38) as a light orange solid. ¹H NMR(DMSO-d₆): δ 8.20-8.17 (dd, J=8.7 Hz, 2H), 7.59-7.56 (d, J=9.0 Hz, 2H),and 3.06-3.01 (m, 2H).

3-(4-Aminophenyl)propionitrile (39)

3-(4-Nitrophenyl)propionitrile (38) (740 mg, 4.2 mmol) was reduced byusing procedure described in Example 5 in methanol (100 mL) with 10%Pd/C as a catalyst to afford 3-(4-aminophenyl)propionitrile (39). ¹H NMR(DMSO-d₆): δ 6.91-6.88 (d, J=9.0 Hz, 2H), 6.49-6.46 (d, J=9.0 Hz, 2H),4.92 (s, 2H), and 2.66 (s, 4H).

(Cyanomethyl)trimethylphosphonium iodide

A solution of triphenylphosphine in toluene (1 mol L⁻¹, 40 mL, 40 mmol)at 0° C. under nitrogen was added to a mixture of toluene (20 mL) andtetrahydrofuran (20 mL). Iodoacetonitrile (2.8 mL, 38.7 mmol) was thenadded dropwise with vigorous stirring. The ice-bath was then removed andthe mixture was stirred at room temperature for an additional of 40hours. The mixture was filtered and the solid was washed with tolueneand dried under reduced pressure to give 8 g of(cyanomethyl)trimethylphosphonium iodide as a light yellow solid. LCMS(m/z): 243.03 (M⁺).

Example 10

2-(4-Nitrophenoxy)acetylhydrazide (41)

To a solution of ethyl 2-(4-nitrophenoxy)acetate (40) (5 g, 24 mmol) inmethanol (75 mL was added hydrazine hydrate (11.8 mL, 38 mmol) at roomtemperature and then the mixture was refluxed for 1 hour. The reactionsolvent was removed under reduced pressure to afford a residue, whichwas washed with dichloromethane (30 mL), followed by with distilledwater (30 mL) and ether (30 mL). The resulting solid was dried underreduced pressure to give 5.7 g of 2-(4-nitrophenoxy)acetylhydrazide (41)as a light yellow solid. ¹H NMR (DMSO-d₆): δ 9.41 (s, 1H), 8.20-8.17 (d,J=9.0 Hz, 2H), 7.15-7.12 (d, J=9.0 Hz, 2H), 4.65 (s, 2H), 4.34 (d, J=6.0Hz, 2H).

N′-Acetyl-2-(4-nitrophenoxy)acetylhydrazide (42)

To a solution of 2-(4-nitrophenoxy)acetylhydrazide (41) (5.7 g, 29.5mmol) in ethyl alcohol (500 mL) were added acetic anhydride (3.9 mL,41.3 mmol) and triethylamine (6.17 mL, 44.3 mmol) at room temperature.The reaction mixture was then refluxed for 1 hour and cooled to roomtemperature. Precipitate obtained was collected by filtration and washedwith cold ethyl alcohol (2×50 mL) to yield 7.5 g ofN′-acetyl-2-(4-nitrophenoxy)acetylhydrazide (42) as a off white solid.¹H NMR (DMSO-d₆): δ 9.84 (s, 1H), 8.21-8.18 (d, J=9.0 Hz, 2H), 7.17-7.14(d, J=9.0 Hz, 2H), 4.77 (s, 2H), 1.90 (br s, 3H).

2-Methyl-5-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole (43)

A mixture of N′-acetyl-2-(4-nitrophenoxy)acetylhydrazide (42) (7.5 g,29.4 mmol) was added to polyphosphoric acid (162 mL) was heated at 120°C. for 1 hour. The reaction mixture was then poured onto crushed ice andextracted with ethyl acetate (3×300 mL). The organic layer was driedover anhydrous sodium sulfate and solvent was removed under reducedpressure. The resulting residue was dissolved in dichloromethane (500mL), washed with aqueous solution of sodium bicarbonate and brine. Afterdrying over anhydrous sodium sulfate, the dichloromethane was removedunder reduced pressure to give crude product, which was purified byflash column chromatography (ethyl acetate: hexanes 3:1 v/v) to give 2.4g of 2-methyl-5-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole (43) as awhite solid. ¹H NMR (DMSO-d₆): δ 8.23-8.20 (d, J=9.0 Hz, 2H), 7.28-7.25(d, J=9.0 Hz, 2H), 5.54 (s, 2H), and 2.52 (s, 3H).

4-[(5-Methyl-1,3,4-oxadiazol-2-yl)methyleneoxy]benzeneamine (44)

2-Methyl-5-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole (43) (1.21 g, 5.13mmol) was reduced by using procedure described in Example 5 to afford1.02 g of 44(5-methyl-1,3,4-oxadiazol-2-yl)methyleneoxy]benzeneamine(44) as a light brown oil. ¹H NMR (CDCl₃): δ 6.85-6.82 (d, J=9.0 Hz,2H), 6.65-6.62 (d, J=9.0 Hz, 2H), 5.132 (s, 2H), and 2.56 (s, 3H).

Example 11

3-(N-4-Methylpiperidin-1-yl)aminosulfonylnitrobenzene (47)

To a solution of 3-chlorosulfonylnitrobenzene (45) (2.21 g, 10 mmol) intetrahydrofuran (100 mL) at 0° C. were added diisopropylethyl amine(1.93 mL, 15 mmol) followed by N-methyl-4-aminopiperidine (46) (1.36 g,12 mmol) and then the reaction mixture was stirred at room temperaturefor 2 hours. The reaction was quenched with water (50 mL), stirred for30 minutes and the tetrahydrofuran layer was separated. The organicsolution was concentrated under reduced pressure. The resulting residuewas taken in dichloromethane (200 mL), washed with aqueous solution ofsodium bicarbonate (2×100 mL) and then brine. The organic layer wasdried over anhydrous sodium sulfate and solvent was removed underreduced pressure to afford the desired product,3-(N-4-methylpiperidin-1-yl)aminosulfonylnitrobenzene (47). LCMS:purity: 93%; MS (m/e): 300 (MH+).

The following compounds were made in a similar fashion to the example 11or by methods described herein or known to skilled artisans.

3-(N-4-Methylpiperidin-1-yl)aminosulfonylaniline (48)

LCMS: purity: 87%; MS (m/e): 270 (MH+).

3-(N-Ethoxycarbonylmethylene)aminosulfonylnitrobenzene

LCMS: purity: 94%; MS (m/e): 289 (MH+).

3-(N-Ethoxycarbonylmethylene)aminosulfonylaniline

LCMS: purity: 88%; MS (m/e): 259 (MH+).

4-(2-N,N-Diethylaminoethyl)aminosulfonylnitrobenzene

¹H NMR (CDCl₃): δ 8.35 (d, 2H, J=8.4 Hz), 8.05 (d, 2H, J=8.4 Hz), 5.02(br s, 1H), 3.01 (t, 2H, J=6.0 Hz), 2.53 (t, 2H, J=6.0 Hz), 2.42 (q, 4H,J=7.2 Hz), 0.94 (t, 6H, J=6.9 Hz), LCMS (m/z): 302 (MH⁺).

3-(2-N,N-Diethylaminoethyl)aminosulfonylnitrobenzene

¹H NMR (CDCl₃): δ 8.69 (t, 1H, J=1.5 Hz), 8.41 (m, 1H), 8.18 (m, 1H),7.72 (t, 1H, J=7.8 Hz), 2.99 (t, 2H, J=6.3 Hz), 2.50 (t, 2H, J=5.4 Hz),2.39 (q, 4H, J=7.2 Hz), 0.92 (t, 6H, J=6.9 Hz), LCMS (m/z): 302 (MH⁺).

4-(2-N,N-Diethylaminoethyl)aminosulfonylaniline

¹H NMR (CDCl₃): δ 7.62 (d, 2H, J=8.4 Hz), 6.67 (d, 2H, J=8.4 Hz), 4.09(s, 2H), 2.91 (t, 2H, J=6.3 Hz), 2.47 (t, 2H, J=5.4 Hz), 2.38 (q, 4H,J=7.2 Hz), 0.92 (t, 6H, J=7.2 Hz), LCMS (m/z): 272 (MH⁺).

3-(2-N,N-Diethylaminoethyl)aminosulfonylaniline

¹H NMR (CDCl₃): δ 7.27-7.13 (m, 3H), 6.82 (m, 1H), 3.91 (s, 2H), 2.94(t, 2H, J=5.7 Hz), 2.45 (t, 2H, J=5.7 Hz), 2.36 (q, 4H, J=7.2 Hz), 0.91(t, 6H, J=7.2 Hz), LCMS (m/z): 272 (MH⁺).

Example 12

methyl 2-(4-nitrophenoxy)isobutyrate (49)

A heterogeneous mixture of 4-nitrophenol (5 g), methyl2-bromoisobutyrate (5.6 mL) and K₂CO₃ (7.5 g) in acetone (60 mL) wasrefluxed overnight. The reaction mixture was then diluted with water(150 mL) and extracted with ethyl acetate (2×100 mL). The organic layerswere evaporated to give methyl 2-(4-nitrophenoxy)isobutyrate (49).

2-(4-nitrophenoxy)isobutyric acid (50)

To a solution of methyl 2-(4-nitrophenoxy)isobutyrate (49) was inmethanol (50 mL) and water (50 mL) was added sodium hydroxide (5 g) atroom temperature. The solution was stirred at room temperature for 30min, then acidified with 1N HCl aqueous to pH ˜3. The aqueous solutionwas extracted with ethyl acetate (2×100 mL). The organic layers werecombined, dried over anhydrous sodium sulfate and solvent was removedunder a reduced pressure to give 2-(4-nitrophenoxy)isobutyric acid (50).

2-(4-nitrophenoxy)-2-methylpropanamide (51)

A mixture of 2-(4-nitrophenoxy)isobutyric acid (50) (5 g), isobutylchloroformate (4.36 mL) and triethylamine (8 mL) in dichloromethane (20mL) was stirred at room temperature for 1 hour. Then 2.0 M ammonia inmethanol (20 mL) was added to the solution. The resulting solution wasstirred at room temperature for 2 hours and then solvent was removedunder reduced pressure. The mixture was purified by recrystallizationfrom EtOAc and hexanes to give 2-(4-nitrophenoxy)-2-methylpropanamide(51).

2-(4-aminophenoxy)-2-methylpropanamide (52)

2-(4-Nitrophenoxy)-2-methylpropanamide (51) was dissolved in methanol(50 mL) and to the solution was added 10% Pd—C (500 mg). The reactionmixture was reacted under hydrogen atmosphere (˜40 psi) for 1 hour. Thecatalyst was then filtered off over Celite. The filtrate was evaporatedunder reduced pressure to give 2-(4-aminophenoxy)-2-methylpropanamide asa white solid (52).

Example 13

4-(Prop-2-ynyloxy)nitrobenzene (X═H, Y═H)

4-Nitrophenol (1.00 g, 7.19 mmol), propargyl bromide (80 wt % intoluene; 0.788 mL, 7.09 mmol), and K₂CO₃ (1.08 g, 7.84 mmol) werestirred in acetone (16.0 mL) at 60° C. for 18 h. The reaction mixturewas cooled to room temperature and diluted with water (200 mL).4-(prop-2-ynyloxy)nitrobenzene was isolated as a white solid by suctionfiltration (1.12 g). ¹H NMR (CDCl₃): δ 8.22 (d, J=9.0 Hz, 2H), 7.05 (d,J=9.0 Hz, 2H), 4.80 (d, J=2.4 Hz, 2H), 2.59 (t, J=2.4 Hz, 1H).

4-(Prop-2-ynyloxy)aniline (X═H, Y═H)

4-(Prop-2-ynyloxy)nitrobenzene (0.910 g, 5.13 mmol), iron (1.42 g, 25.3mmol), and NH₄Cl (0.719 g, 12.8 mmol) were vigorously stirred inEtOH/water (1:1, 55 mL) at 70° C. for 15 minutes. The reaction mixturewas filtered hot through Celite and concentrated in vacuo. The residuewas suspended in 10% 2N ammoniacal methanol in dichloromethane,sonicated, and filtered through Celite. Concentration gave4-(prop-2-ynyloxy)aniline as a brown oil which was used without furtherpurification. In general, isolated prop-2-ynyloxyanilines were unstableand were therefore used immediately after the second filtration. ¹H NMR(CDCl₃): δ 6.82 (d, J=8.7 Hz, 2H), 6.64 (d, J=8.7 Hz, 2H), 4.61 (d,J=2.4 Hz, 2H), 2.50 (t, J=2.4 Hz, 1H).

The following compounds were made in a similar fashion to the example13.

3-Methyl-4-(prop-2-ynyloxy)nitrobenzene (X=Me, Y═H)

¹H NMR (CDCl₃): δ 8.10 (dd, J=3.0 and 9.0 Hz, 1H), 7.01 (d, J=9.0 Hz,1H), 4.83 (d, J=2.4 Hz, 2H), 2.58 (t, J=2.4 Hz, 1H), 2.31 (s, 3H).

3-Chloro-4-(prop-2-ynyloxy)nitrobenzene (X═Cl, Y═H)

¹H NMR (CDCl₃): δ 8.31 (d, J=2.7 Hz, 1H), 8.17 (dd, J=2.7 and 9.0 Hz,1H), 7.17 (d, J=9.0 Hz, 1H), 4.90 (d, J=2.7 Hz, 2H), 2.63 (t, J=2.7 Hz,1H).

3-Fluoro-4-(prop-2-ynyloxy)nitrobenzene (X═F, Y═H)

¹H NMR (CDCl₃): δ 8.07 (ddd, J=1.5, 2.7, and 9.3 Hz, 1H), 8.01 (dd,J=2.7 and 10.5 Hz, 1H), 7.20 (t, J=8.7 Hz, 1H), 4.89 (d, J=2.1 Hz, 2H),6.23 (t, J=2.1 Hz, 1H).

4-(But-2-ynyloxy)nitrobenzene (X═H, Y=Me)

¹H NMR (CDCl₃): δ 8.21 (d, J=9.0 Hz, 2H), 7.03 (d, J=9.0 Hz, 2H), 4.75(q, J=2.4 Hz, 2H), 1.88 (t, J=2.4 Hz, 3H).

3-(Prop-2-ynyloxy)nitrobenzene

¹H NMR (CDCl₃): δ 7.87 (ddd, J=0.9, 2.1, and 8.1 Hz, 1H), 7.83 (t, J=2.1Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 7.30 (ddd, J=0.6, 2.4, and 8.4 Hz, 1H),4.79 (d, J=2.4 Hz, 2H), 2.58 (t, J=2.4 Hz, 1H).

Example 14

2-Aminocarbonyl-5-nitrobenzofuran

A dry reaction flask equipped with a magnetic stirring bar, nitrogeninlet and rubber septum was charged with 2-carboxy-5-nitrobenzofuran(0.414 g, 2 mmol) and CH₂Cl₂ (100 mL). To this was added DMF (0.1 mL)followed by a slow addition of oxaloyl chloride (0.519 mL, 6 mmol) overthe period of 5 minutes at 0° C. The reaction mixture was furtherstirred for 30 minutes by the time the formation of a clear solution wasobserved. The resulting clear solution was concentrated under a reducedpressure and dried under high vacuum for 30 minutes. The resultingresidue was suspended in EtOAc (25 mL), cooled to 10° C., to it wasadded NH₄OH (30% solution, 25 mL) and stirred at room temperature for 24h. The organic phase was separated and dried over anhydrous sodiumsulfate and solvent was removed to give2-aminocarbonyl-5-nitrobenzofuran. ¹H NMR (DMSO-d6): δ 8.75 (d, 1H,J=2.7 Hz), 8.28 (m, 2H), 7.86 (d, 1H, J=9.0 Hz), 7.83 (bs, 1H), 7.72 (s,1H); LCMS: purity: 93%, MS (m/e): 206 (M⁺).

2-Cyano-5-nitrobenzofuran

A heterogeneous solution of 2-aminocarbonyl-5-nitrobenzofuran (0.206 g,1 mmol) in POCl₃ (5 mL) was heated at 100° C. for 24 to give a clearsolution. The resulting clear solution was carefully poured overice-water to give a solid mass which was isolated by filtration followedby washing with water to give 2-cyano-5-nitrobenzofuran. ¹H NMR(DMSO-d6): δ 8.80 (d, 1H, J=2.4 Hz), 8.42 (dd, 1H, J=2.7 and 9.0 Hz),8.27 (s, 1H), 7.99 (d, 1H, J=8.7 Hz); LCMS: purity: 98%, MS (m/e): 189(MH⁺).

5-Amino-2-cyanobenzofuran

A heterogeneous reaction mixture of 2-cyano-5-nitrobenzofuran (0.150 g,0.789 mmol), iron powder (0.220 g, 3.9 mmol), NH₄Cl (0.221 g, 3.9 mmol)in EtOH/H₂O (5 mL each) was vigorously stirred at 60-70° C. for 1 hour.The resulting solution was filtered through a pad of Celite when hot andthen washed with methanol. The filtrated was concentrated to drynessunder a vacuum and resuspended into H₂O (20 mL), saturated and the solidwas isolated by filtration to obtain 5-amino-2-cyanobenzofuran. ¹H NMR(DMSO-d6): δ 7.80 (s, 1H), 7.36 (d, 1H, J=8.7 Hz), 6.86 (dd, 1H, J=2.7and 9.0 Hz), 6.76 (d, 1H, J=2.1 Hz), 5.16 (bs, 2H); LCMS: purity: 95%,MS (m/e): 159 (MH⁺).

Example 15

3-Aminosulfonyl-4-methoxy-5-methyl-aniline

A dry reaction flask equipped with a magnetic stirring bar, nitrogeninlet and reflux condenser was charged with 2-fluoro-5-nitrotoluene(6.20 g, 40 mmol) followed by chlorosulfonic acid (10.60 mL, 160 mmol)at 0° C., and then the reaction was stirred at 100° C. for 24 hours.After cooling it to the room temperature, the reaction was poured overice-water (Caution!) and extracted with ethyl acetate (3×200 mL).Removal solvent under a reduced pressure afforded3-chlorosulfonyl-4-fluoro-5-methylnitrobenzene intermediate, which wasstirred in EtOAc (50 mL) and NH₄OH (30%, 50 mL) for 2-3 hours. Theseparated organic phase was then evaporated to afford a crude material,which was purified by column chromatography (silica gel, hexanes then10-20% EtOAc in hexanes) to afford3-aminosulfonyl-4-fluoro-5-methylnitrobenzene. LCMS: purity: 96%; MS(m/e): 235 (MH⁺).

The resulting 3-aminosulfonyl-4-fluoro-5-methylnitrobenzene (0.940 g, 4mmol) was stirred with 25% methanolic NaOMe (1.00 mL) at 60° C. forovernight. The resulting solution was then filtered through a pad ofCelite, washed with methanol and the methanolic solution wasconcentrated to give 3-aminosulfonyl-4-methoxy-5-methylnitrobenzene.LCMS: purity: 100%, MS (m/e): 247 (MH⁺).

The reduction of 3-aminosulfonyl-4-methoxy-5-methylnitrobenzene (0.740g, 3 mmol) using iron powder (0.81 g, 15 mmol), NH₄Cl (0.81 g, 15 mmol)in ethanol (100 mL):water (25 mL) at 60° C. for 1 hour followed byfiltration through a pad of Celite gave aqueous alcoholic solution.Concentration of it followed by dilution with water afforded a solidmass, which was isolated by filtration to give3-aminosulfonyl-4-methoxy-5-methylaniline. ¹H NMR (DMSO-d6): δ 6.90 (bs,1H), 6.55 (bs, 1H), 5.1 (bs, 2H), 3.65 (s, 3H), 2.15 (s, 3H), LCMS:purity: 94%, MS (m/e): 217 (MH⁺).

The following compounds were made in a similar fashion to the methodsdescribed herein or known to skilled artisans.

4-(4-Nitrophenoxymethyl)-2-methylthiazole

¹H NMR (CDCl₃, 300 MHz): δ 8.19 (d, 2H, J=9.0 Hz), 7.17 (s, 1H), 7.04(d, 2H, J=9.3 Hz), 5.22 (s, 2H), 2.74 (s, 3H); LCMS (m/z): 251 (MH⁺).

3-[(4-Nitrophenoxy)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.68 (d, 1H, J=2.1 Hz), 8.62 (dd, 1H, J=1.5and 4.8 Hz), 8.21 (d, 2H, J=9.0 Hz), 7.76 (m, 1H), 7.35 (dd, 1H, J=4.5and 7.8 Hz), 7.03 (d, 2H, J=9.0 Hz), 5.17 (s, 2H); LCMS (m/z): 231(MH⁺).

2-[(4-Nitrophenoxy)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.61 (d, 1H, J=4.8 Hz), 8.19 (d, 2H, J=9.0Hz), 7.72 (m, 2H), 7.46 (d, 1H, J=7.8 Hz), 7.25 (m, 1H), 7.05 (d, 2H,J=9.3 Hz), 5.28 (s, 2H); LCMS (m/z): 231 (MH⁺).

2-[(4-Nitrophenoxy)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.60 (d, 1H, J=4.5 Hz), 8.04 (m, 2H), 7.73(m, 1H), 7.48 (d, 1H, J=8.1 Hz), 7.25 (m, 1H), 6.92 (d, 1H, J=9.3 Hz),5.30 (s, 2H), 2.39 (s, 3H); LCMS (m/z): 245 (MH⁺).

3-[(3-Nitrophenoxy)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.69 (d, 1H, J=2.1 Hz), 8.61 (d, 1H, J=4.5Hz), 7.81 (m, 3H), 7.45 (t, 1H, J=8.1 Hz), 7.36-7.24 (m, 2H), 5.15 (s,2H); LCMS (m/z): 231 (MH⁺).

4-[(4-Nitrophenoxy)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.61 (d, 2H, J=5.4 Hz), 8.21 (d, 2H, J=9.0Hz), 7.33 (d, 2H, J=5.4 Hz), 7.02 (d, 2H, J=9.0 Hz), 5.18 (s, 2H); LCMS(m/z): 231 (MH⁺).

Example 16

7-nitro-4-(3-pyridylmethyl)benz[1,4]oxazine

To a dry reaction flask equipped with a reflux condenser, a magneticstirring bar and a rubber septum with a N₂ inlet was placed7-nitrobenz[1,4]oxazine (1.0 g, 5.55 mmol), tetrabutyl ammonium chloride(56 mg), powdered NaOH (0.58 g) in dry DMF (10 mL). The reaction mixturewas stirred at room temperature for 30 minutes. 3-(Bromomethyl)-pyridinehydrobromide (1.40 g, 5.55 mmol) was added. The reaction mixture washeated at 80° C. for over night, cooled to room temperature, poured inwater (200 mL), left aside for 2 h, added ethyl acetate (200 mL). Theorganic layer was washed with water (2×200 mL), brine (200 mL), dried(Na₂SO₄) and concentrated. The solid was purified by silica gel column,eluted with EtOAc to give 0.67 g (44%) of the desired7-nitro-4-(3-pyridylmethyl)benz[1,4]oxazine. ¹H NMR (CDCl₃, 300 MHz): δ8.56 (d, 1H, J=4.8 Hz), 8.53 (s, 1H), 7.72 (m, 2H), 7.53 (m, 1H), 7.28(dd, 1H, J=5.1 and 7.8 Hz), 6.57 (d, 1H, J=9.0 Hz), 4.61 (s, 2H), 4.29(t, 2H, J=4.2 Hz), 3.59 (t, 2H, J=4.5 Hz); LCMS (m/z): 272 (MH⁺).

Example 17

4-(4-pyridinyloxy)-1-nitrobenzene

To a solution of 4-hydroxypyridine (4.42 g, 45.8 mmol) and1-fluoro-4-nitrobenzene (4.89 mL, 45.8 mmol) in anhydrous DMF (50 mL)was added anhydrous K₂CO₃ (13.0 g, 91.6 mmol) in one portion. Themixture was heated at the reflux temperature with stirring for 24 h,cooled to room temperature and poured in water (300 mL). The solid thatseparated was filtered, washed with water and dried well under highvacuum to yield 8.9 g (90%) of desired product,4-(4-pyridinyloxy)-1-nitrobenzene. ¹H NMR (CDCl₃, 300 MHz): δ 8.36 (d,2H, J=9.0 Hz), 8.11 (d, 2H, J=8.1 Hz), 7.83 (d, 2H, J=9.0 Hz), 6.27 (d,2H, J=7.8 Hz); LCMS (m/z): 217 (MH⁺).

Example 18

4-(4-nitrobenzoyl)thiomorpholine (X═S)

To a stirred solution of thiomorpholine (2.00 mL, 20 mmol) and Et₃N (5.0mL) in CH₂Cl₂ (60 mL) was added drop wise a solution of 4-nitrobenzoylchloride (3.71 g, 20 mmol) in CH₂Cl₂ (50 mL) at 0° C. The reaction wasallowed to stir at room temperature for over night and then washed witha saturated NaHCO₃ solution (2×75 mL), and water (2×75 mL). The CH₂Cl₂layer was dried (Na₂SO₄) and filtered and concentrated. Finally driedunder high vacuum to afford 5.027 g (99%) of the4-(4-nitrobenzoyl)thiomorpholine. ¹H NMR (CDCl₃, 300 MHz): δ 8.28 (d,2H, J=9.0 Hz), 7.54 (d, 2H, J=8.7 Hz), 4.04 (br s, 2H), 3.61 (br s, 2H),2.75 (br s, 2H), 2.57 (br s, 2H); LCMS (m/z): 253 (MH⁺).

The following compounds were made in a similar fashion to the example18, methods described herein or known to skilled artisans.

1-Methanesulfonyl-4-(4-nitrobenzoyl)piperazine

¹H NMR (CDCl₃, 300 MHz): δ 8.29 (d, 2H, J=8.4 Hz), 7.58 (d, 2H, J=8.4Hz), 3.91 (br s, 2H), 3.52 (br s, 2H), 3.33 (br s, 2H), 3.23 (br s, 2H),2.83 (s, 3H); LCMS (m/z): 314 (MH⁺).

4-(4-Nitrobenzoyl)thiomorpholine-1,1-dioxide

¹H NMR (CDCl₃, 300 MHz): δ 8.32 (d, 2H, J=8.4 Hz), 7.60 (d, 2H, J=9.0Hz), 4.08 (br s, 4H), 3.08 (br s, 4H); LCMS (m/z): 285 (MH⁺).

1-Acetyl-4-(4-nitrobenzoyl)piperazine

¹H NMR (CDCl₃, 300 MHz): δ 8.29 (d, 2H, J=8.7 Hz), 7.58 (d, 2H, J=8.4Hz), 3.59 (m, 8H), 2.14 (s, 3H); LCMS (m/z): 277 (MH⁺).

4-(4-Aminophenoxymethyl)-2-methylthiazole

¹H NMR (CDCl₃, 300 MHz): δ 7.10 (s, 1H), 6.81 (d, 2H, J=8.7 Hz), 6.62(d, 2H, J=9.0 Hz), 5.06 (s, 2H), 3.43 (s, 2H), 2.72 (s, 3H); LCMS (m/z):221 (MH⁺).

3-[(4-Aminophenoxy)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.63 (d, 1H, J=2.1 Hz), 8.54 (d, 1H, J=5.1Hz), 7.74 (d, 1H, J=7.5 Hz), 7.29 (dd, 1H, J=5.1 and 7.8 Hz), 6.79 (d,2H, J=8.7 Hz), 6.63 (d, 2H, J=8.7 Hz), 4.99 (s, 2H), 3.44 (br s, 2H);LCMS (m/z): 201 (MH⁺).

3-[(3-Aminophenoxy)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.64 (d, 1H, J=2.1 Hz), 7.75 (m, 1H), 7.29(dd, 1H, J=4.8 and 7.8 Hz), 7.05 (t, 1H, J=8.4 Hz), 6.33 (m, 3H), 5.02(s, 2H), 3.67 (br s, 2H); LCMS (m/z): 201 (MH⁺).

2-[(4-Aminophenoxy)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.56 (m, 1H), 7.67 (m, 1H), 7.49 (d, 1H,J=7.8 Hz), 7.18 (m, 1H), 6.80 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.7 Hz),5.12 (s, 2H), 3.43 (br s, 2H); LCMS (m/z): 201 (MH⁺).

4-[(4-Aminophenoxy)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.56 (d, 2H, J=6.0 Hz), 7.31 (d, 2H, J=6.0Hz), 6.76 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.6 Hz), 5.01 (s, 2H), 3.31(br s, 2H); LCMS (m/z): 201 (MH⁺).

2-[(4-Aminophenoxy-2-methyl)methyl]pyridine

¹H NMR (CDCl₃, 300 MHz): δ 8.55 (d, 1H, J=4.8 Hz), 7.68 (m, 1H), 7.53(d, 1H, J=7.5 Hz), 7.18 (m, 1H), 6.67 (d, 1H, J=8.4 Hz), 6.55 (d, 1H,J=3.0 Hz), 6.44 (dd, 1H, J=2.7 and 8.5 Hz), 5.11 (s, 2H), 3.23 (br s,2H), 2.26 (s, 3H); LCMS (m/z): 215 (MH⁺).

7-Amino-4-(3-pyridylmethyl)benzo[1,4]oxazine

LCMS (m/z): 242 (MH⁺).

Example 19

4-(4-aminobenzoyl)thiomorpholine

To a stirred solution of 4-(4-nitrobenzoyl)thiomorpholine (1.26 g, 5mmol) in ethanol (80 mL) and water (20 mL) was added NH₄Cl (2.65 g) andheated to 80° C. To this heterogeneous reaction mixture at 80° C. wasadded iron powder (2.75 g) portion wise manner under a vigorous stirringin nitrogen atmosphere and the stirring was continued for 2 h. Thereaction mixture was filtered through a Celite pad when hot and washedthe pad with methanol. The filtrate was concentrated, diluted withwater, extracted with CH₂Cl₂ (3×75 mL), dried (Na₂SO₄), filtered andconcentrated. Finally dried under high vacuum to afford 1.11 g (100%) ofthe 4-(4-aminobenzoyl)thiomorpholine. ¹H NMR (CDCl₃, 300 MHz): δ 7.21(d, 2H, J=8.4 Hz), 6.64 (d, 2H, J=8.1 Hz), 3.86 (br s, 6H), 2.64 (t, 4H,J=4.5 Hz); LCMS (m/z): 223 (MH⁺).

The following compounds were made in a similar fashion to the example19.

1-Methanesulfonyl-4-(4-aminobenzoyl)piperazine

¹H NMR (CDCl₃, 300 MHz): δ 7.26 (d, 2H, J=7.8 Hz), 6.65 (d, 2H, J=8.4Hz), 3.92 (br s, 2H), 3.75 (t, 4H, J=4.8 Hz), 3.23 (t, 4H, J=4.8 Hz),2.79 (s, 3H); LCMS (m/z): 284 (MH⁺).

4-(4-Aminobenzoyl)thiomorpholine-1,1-dioxide

¹H NMR (CDCl₃, 300 MHz): δ 7.27 (d, 2H, J=8.7 Hz), 6.65 (d, 2H, J=8.7Hz), 4.09 (t, 4H, J=5.4 Hz), 3.97 (s, 2H), 3.05 (t, 4H, J=5.1 Hz),; LCMS(m/z): 255 (MH⁺).

1-Acetyl-4-(4-aminobenzoyl)piperazine

¹H NMR (CDCl₃, 300 MHz): δ 7.26 (d, 2H, J=7.2 Hz), 6.65 (d, 2H, J=7.8Hz), 3.90 (s, 2H), 3.60 (m, 8H), 2.12 (s, 3H); LCMS (m/z): 248 (MH⁺).

4-(4-pyridinyloxy)aniline

¹H NMR (DMSO d₆, 300 MHz): δ 7.76 (br s, 2H), 7.10 (br s, 2H), 6.61 (brs, 2H), 6.13 (br s, 2H), 5.37 (s, 2H); LCMS (m/z): 187 (MH⁺).

1-Cyanomethoxy-2,3-dimethoxy-5-nitrobenzene

To a solution of 1.5 g of (±)-2,3-dimethoxy-5-nitrophenol in 25 mL ofacetone at room temperature was added 7.8 g cesium carbonate and then0.75 mL bromoacetonitrile was added slowly dropwise. The reactionmixture was filtered, the filtrate evaporated and the resulting residuewas partitioned between 1N HCl solution and EtOAc. The aqueous phase wasextracted with EtOAc and the combined organics washed with bicarbonatesolution, brine then dried over MgSO₄. The solvent was removed by rotaryevaporation and the crude material purified by column chromatography(hexanes/EtOAc) to yield 1.4 g 78% yield of the desired product1-cyanomethoxy-2,3-dimethoxy-5-nitrobenzene. ¹H NMR (DMSO-d6): δ 7.78(d, 2H, J=4.5 Hz), 7.64 (d, 2H, J=4.5 Hz), 5.38 (s, 2H), 3.92 (s, 3H),3.82 (s, 3H); LCMS: purity 93%; MS (m/e): 239 (MH⁺).

3-Cyanomethoxy-4,5-dimethoxyaniline

A solution of 1.4 g of 1-cyanomethoxy-2,3-dimethoxy-5-nitrobenzene in 75mL ethanol with 1.65 g of iron and 1.65 g of ammonium chloride wasrefluxed for 4 h, cooled to RT, diluted with DCM, filtered, extractedwith DCM and the combined organic were dried with sodium sulfate andevaporated to give 1 g 82% of the desired product3-cyanomethoxy-4,5-dimethoxyaniline, MS (m/e): 209 (MH⁺).

The following compounds were made in a similar fashion to the aboveexample.

3-(2-Fluoro-4-nitrophenyl)propionitrile

¹H NMR (DMSO-d₆): δ 8.12-8.06 (t, 2H), 7.72-7.66 (t, 1H), 3.07-3.02 (t,2H), 2.91-2.86 (t, 2H), LCMS: 196.10 (MH⁺).

3-(4-Amino-2-fluorophenyl)propionitrile

¹H NMR (DMSO-d₆): δ 8.41 (s, 2H), 7.13-7.07 (t, 1H), 6.57-6.54 (d,J=10.5 Hz, 2H), 2.77-2.71 (m, 4H), LCMS: 164.02 (MH⁺).

3-(2-Methyl-4-nitrophenyl)propionitrile

¹H NMR (DMSO-d₆): δ 8.06 (s, 1H), 8.03-8.00 (d, J=8.4 Hz, 1H), 7.50-7.48(d, J=8.1 Hz, 1H), 3.03-2.98 (t, 2H), 2.88-2.83 (t, 2H), 2.41 (s, 3H),LCMS: 193.12 (MH+).

3-(2-Chloro-4-nitrophenyl)propionitrile

LCMS: 211.11 (MH+).

3-(4-Amino-2-chlorophenyl)propionitrile

LCMS: 181.04 (MH⁺).

Example 20

2-Chloro-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(54, X═H)

5-Methyl-3-(4-aminophenoxymethyl)isoxazole (4, X═H, 1.94 g)2,4-dichloro-5-fluoropyrimidine (53) (4.0 g) were dissolved in MeOH:H₂O(9:1, v/v, 400 mL). The reaction was allowed to stir at room temperature24 hours, MeOH was removed under reduced pressure, the residue wasbasified with aqueous saturated solution of sodium bicarbonate (100 mL),water (300 mL), extracted with EA (3×300 mL), dried (Na₂SO₄) and solventwas removed under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to provided 1.93 g of2-chloro-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(54, X═H) as a white solid. ¹H NMR (DMSO-d6): δ 9.85 (s, 1H), 8.24 (d,1H, J=3.6 Hz), 7.54 (d, 2H, J=8.7 Hz), 7.02 (d, 2H, J=9.0 Hz), 6.31 (s,1H), 5.12 (s, 2H), 2.40 (s, 3H); LCMS (m/z): 335 (MH⁺).

The following compounds were made in a similar fashion to the example20.

2-Chloro-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(54, X═CH₃)

¹H NMR (CDCl₃): δ 7.99 (d, 1H, J=3.0 Hz), 7.42 (dd, 1H, J=2.4 and 8.7Hz), 7.30 (d, 1H, J=2.4 Hz), 6.89 (d, 2H, J=8.4 Hz), 6.09 (s, 1H), 5.10(s, 2H), 2.44 (s, 3H), 2.26 (s, 3H); LCMS (m/z): 350 (MH⁺).

2-Chloro-5-fluoro-N4-[3-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(54, X═F)

LCMS: purity: 93%; MS (m/e): 354 (MH+).

2-Chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine(11)

¹H NMR (DMSO-d6): δ 9.91 (s, 1H), 8.26 (d, 1H, J=3.5 Hz), 7.56 (d, 2H,J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz), 5.46 (s, 2H), 2.34 (s, 3H); LCMS(m/z): 336 (MH⁺).

2-Chloro-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)ethylenephenyl]-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 9.92 (s, 1H) 8.28-8.27 (d, J=3.0 Hz, 1H), 7.57-7.54(d, J=9.0 Hz, 2H), 7.25-7.22 (d, J=9.0 Hz, 2H) 3.23-3.18 (m, 2H),3.07-3.02 (m, 2H), 2.29 (s, 3H); LCMS (m/z): 334.27 (M⁺).

2-Chloro-N4-(3-cyano-4-methylphenyl)-5-fluoro-4-pyrimidineamine

LCMS: 263.23 (MH⁺).

2-Chloro-N4-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidineamine

LCMS: (m/z): 276.16 (MH⁺).

2-Chloro-N4-(3-cyano-4-fluorophenyl)-5-fluoro-4-pyrimidineamine

LCMS (m/z): 267.20 (MH⁺).

2-Chloro-5-fluoro-N4-(2-methylindol-5-ylmethylene)-4-pyrimidineamine

LCMS (m/z): 291.32 (MH⁺).

Example 21

N4-(4-aminocarbonylmethyleneoxy)phenyl-2-chloro-5-fluoro-4-pyrimidineamine(55)

A mixture of 4-(aminocarbonylmethyleneoxy)aniline (21) (5 g) and2,6-dichloro-5-fluoropyrimidine (53) (6 g) in methanol (10 mL) and water(1 mL) was stirred at room temperature overnight. Then methanol wasremoved under reduced pressure. The remaining aqueous solution wasacidified with 1 N HCl (80 mL). The white precipitate was collected byfiltration, washed with water (3×50 mL) and dried to giveN4-(4-aminocarbonylmethyleneoxy)phenyl-2-chloro-5-fluoro-4-pyrimidineamine(55). ¹H NMR (CDCl₃): δ 8.07 (d, 1H, J=2.7 Hz), 7.52 (t, 1H, J=2.4 Hz),7.30 (d, 1H, J=8.1 Hz), 7.19 (m, 1H), 6.96 (br s, 1H), 6.79 (m, 1H),5.29 (s, 2H), 2.44 (s, 3H); LCMS (m/z): 336 (MH⁺).

2-Chloro-N4-(4-cyanomethyleneoxy)phenyl-5-fluoro-4-pyrimidineamine (56)

To a solution ofN4-(4-aminocarbonylmethyleneoxy)phenyl-2-chloro-5-fluoro-4-pyrimidineamine(55) (2 g) in THF (20 mL) was added trifluoroacetic anhydride (1.9 mL)and pyridine (1.65 mL) at room temperature. The reaction solution wasstirred at room temperature overnight and then diluted with ethylacetate (100 mL). The organic layer was washed with aqueous solution ofpotassium carbonate (2×100 mL), 1 N HCl (100 mL) and water (100 mL). Theethyl acetate layer was separated, dried over anhydrous sodium sulfateand solvent was evaporated under reduced pressure to give2-chloro-N4-(4-cyanomethyleneoxy)phenyl-5-fluoro-4-pyrimidineamine (56).

The following compounds were made in a similar fashion to the example21.

-   2-chloro-5-fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-4-pyrimidineamine-   N4-[4-(1-aminocarbonyl-1-methyl)ethoxy]phenyl-2-chloro-5-fluoro-4-pyrimidineamine-   2-chloro-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-4-pyrimidineamine-   2-Chloro-N4-[4-(cyanoethylene)phenyl]-5-fluoro-4-pyrimidineamine

N4-[4-(1-Benzyl-3-methyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-2-chloro-5-fluoro-4-pyrimidineamine

LCMS: purity: 95%; MS (m/e): 424 (MH+).

2-Chloro-N4-[4-(1,3-dimethyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-5-fluoro-4-pyrimidineamine

LCMS: purity: 95%; MS (m/e): 424 (MH+).

2-Chloro-5-fluoro-N4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)methyleneoxyphenyl]-4-pyrimidineamine

¹H NMR (CDCl₃): δ 8.04-8.03 (d, J=3.0 Hz, 1H), 7.56-7.53 (d, J=9.0 Hz,2H), 7.06-7.03 (d, J=9.0 Hz, 2H), 5.24 (s, 2H), and 2.58 (s, 3H).

N4-[2-(tert-Butylcarbonyl)amino-3-methoxypyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine(65)

A homogeneous mixture of6-amino-2-(tert-butylcarbonyl)amino-3-methoxypyridine (35) (1.5 g, 6.72mmol) and 2,4-dichloro-5-fluoropyrimidine (53) (1.68 g, 10 mmol) inmethanol:water (20 mL, each) was stirred at 60° C. for 48 hours. Thereaction mixture upon dilution with water (100 mL) gave a solid, whichwas isolated by filtration to obtainN4-[2-(tert-butylcarbonyl)amino-3-methoxypyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine.LCMS: purity: 89%; MS (m/z): 354 (MH⁺).

Example 22

2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (X═H,Y═H)

Crude 4-(prop-2-ynyloxy)aniline (0.750 g, 5.10 mmol) and2,4-dichloro-5-fluoropyrimidine (1.27 g, 0.760 mmol) were stirred inMeOH/water (4:1, 35 mL) at room temperature for 18 h. The reactionmixture was diluted with EtOAc (200 mL) and washed with 1N HCl (50 mL)and brine (50 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, hexanes ramped to EtOAc:hexanes (1:10)) to provide2-chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine as alight brown solid (0.514 g). ¹H NMR (CDCl₃): δ 8.03 (d, J=2.7 Hz, 1H),7.53 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.86 (s, 1H), 4.71 (d,J=2.4 Hz, 2H), 2.55 (t, J=2.4 Hz, 1H); LCMS: purity: 99%; MS (m/e): 279(MH⁺).

The following compounds were made in a similar fashion to the example22, methods described herein or known to skilled artisans.

2-Chloro-5-fluoro-N4-[3-methyl-4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine(X=Me, Y═H)

¹H NMR (CDCl₃): δ 8.01 (d, J=2.7 Hz, 1H), 7.50 (dd, J=2.7 and 8.7 Hz,1H), 7.50 (dd, J=2.7 and 8.7 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 6.97 (d,J=8.7 Hz, 1H), 6.82 (s, 1H), 4.72 (d, J=2.4 Hz, 2H), 2.53 (t, J=2.4 Hz,1H), 2.28 (s, 3H); LCMS: purity: 99%; MS (m/e): 293 (MH⁺).

2-Chloro-N4-[3-chloro-4-(prop-2-ynyloxy)phenyl]-5-fluoro-4-pyrimidineamine(X═Cl, Y═H)

¹H NMR (CDCl₃): δ 8.06 (d, J=2.7 Hz, 1H), 7.66 (d, J=2.7 Hz, 1H), 7.54(dd, J=3.0 and 9.3 Hz, 1H), 7.12 (d, J=9.3 Hz, 1H), 6.86 (s, 1H), 4.79(d, J=2.4 Hz, 2H), 2.57 (t, J=2.4 Hz, 1H); LCMS: purity: 98%; MS (m/e):313 (MH⁺).

2-Chloro-5-fluoro-N4-[3-fluoro-4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine(X═F, Y═H)

¹H NMR (CDCl₃): δ 8.07 (d, J=2.7 Hz, 1H), 7.59 (dd, J=2.7 and 12.6 Hz,1H), 7.28-7.24 (m, 1H), 7.13 (t, J=8.7 Hz, 1H), 6.89 (s, 1H), 4.78 (d,J=2.4 Hz, 2H), 2.56 (t, J=2.4 Hz, 1H); LCMS: purity: 99%; MS (m/e): 297(MH⁺).

N4-[4-(But-2-ynyloxy)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine (X═H,Y=Me)

¹H NMR (CDCl₃): δ 8.02 (d, J=2.7 Hz, 1H), 7.52 (d, J=9.0 Hz, 2H), 7.00(d, J=9.0 Hz, 2H), 6.85 (s, 1H), 4.66 (q, J=2.4 Hz, 2H), 1.89 (t, J=2.4Hz, 3H); LCMS: purity: 98%; MS (m/e): 293 (MH⁺).

2-Chloro-5-fluoro-N4-[3-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine

¹H NMR (CDCl₃): δ 8.08 (d, J=2.7 Hz, 1H), 7.49 (t, J=2.1 Hz, 1H), 7.31(t, J=8.1 Hz, 1H), 7.16 (ddd, J=0.9, 2.1, and 8.1 Hz, 1H), 6.94 (s, 1H),6.80 (ddd, J=0.9, 2.4, and 8.1 Hz, 1H), 4.74 (d, J=2.4 Hz, 2H), 2.57 (t,J=2.4 Hz, 1H); LCMS: purity: 98%; MS (m/e): 279 (MH⁺).

2-Chloro-N4-(2-cyanobenzofuran-5-yl)-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d6): δ 10.14 (s, 1H), 8.32 (d, 1H, J=3.6 Hz), 8.14 (s, 1H),8.12 (d, 1H, J=1.8 Hz), 7.77 (m, 2H); LCMS: purity: 94%, MS (m/e): 290(MH⁺).

2-Chloro-5-fluoro-N-[4-(3-pyridinylmethyl)benz[1,4]oxazin-7-y]-4-pyrimidineamine

¹H NMR (CDCl₃, 300 MHz): δ 8.56 (d, 1H, J=1.8 Hz), 8.52 (dd, 1H, J=1.5and 4.6 Hz), 7.95 (d, 1H, J=3.0 Hz), 7.62 (m, 1H), 7.26 (m, 1H), 7.11(d, 1H, J=2.7 Hz), 6.98 (dd, 1H, J=2.4 and 8.5 Hz), 6.90 (d, 1H, J=2.1Hz), 6.60 (d, 1H, J=8.7 Hz), 4.29 (m, 2H), 3.36 (m, 2H); LCMS (m/z): 372(MH⁺).

2-Chloro-5-fluoro-N-[4-(3-pyridinyl)methyleneoxyphenyl]-4-pyrimidineamine

¹H NMR (CDCl₃, 300 MHz): δ 8.66 (s, 1H), 8.58 (d, 1H, J=4.8 Hz), 8.00(d, 1H, J=2.1 Hz), 7.77 (d, 1H, J=8.1 Hz), 7.52 (d, 2H, J=9.0 Hz), 7.32(dd, 1H, J=5.1 and 7.6 Hz), 6.98 (d, 3H, J=8.4 Hz), 5.08 (s, 2H); LCMS(m/z): 331 (MH⁺).

2-Chloro-5-fluoro-N-[4-(4-pyridinylmethyl)phenyl]-4-pyrimidineamine

¹H NMR (CDCl₃, 300 MHz): δ 8.49 (d, 2H, J=6.0 Hz), 8.04 (d, 1H, J=3.0Hz), 7.58 (d, 2H, J=8.4 Hz), 7.19 (d, 2H, J=8.1 Hz), 7.09 (d, 3H, J=5.4Hz), 3.96 (s, 2H); LCMS (m/z): 315 (MH⁺).

2-Chloro-5-fluoro-N-[3-(3-pyridinyl)methyleneoxyphenyl]-4-pyrimidineamine

LCMS (m/z): 331 (MH⁺).

2-Chloro-5-fluoro-N-[4-(2-methylithiazol-4-yl)methyleneoxyphenyl]-4-pyrimidineamine

¹H NMR (CDCl₃, 300 MHz): δ 8.00 (d, 1H, J=2.1 Hz), 7.50 (d, 2H, J=9.0Hz), 7.15 (s, 1H), 6.99 (d, 2H, J=9.0 Hz), 6.89 (br s, 1H), 5.14 (s,2H), 2.73 (s, 3H); LCMS (m/z): 351 (MH⁺).

2-Chloro-5-fluoro-N-[4-(2-pyridinyl)methyleneoxyphenyl]-4-pyrimidineamine

¹H NMR (CDCl₃, 300 MHz): δ 8.58 (d, 1H, J=4.5 Hz), 8.00 (d, 1H, J=3.0Hz), 7.71 (m, 1H), 7.49 (m, 3H), 7.22 (m, 1H), 6.99 (d, 2H, J=9.0 Hz),6.96 (br s, 1H), 5.19 (s, 2H); LCMS (m/z): 331 (MH⁺).

2-Chloro-5-fluoro-N-[4-(4-pyridinyl)methyleneoxyphenyl]-4-pyrimidineamine

¹H NMR (CDCl₃, 300 MHz): δ 8.60 (d, 2H, J=6.0 Hz), 8.01 (d, 1H, J=2.7Hz), 7.52 (d, 2H, J=9.0 Hz), 7.35 (m, 2H), 6.96 (d, 2H, J=9.0 Hz), 6.92(br s, 1H), 5.10 (s, 2H); LCMS (m/z): 331 (MH⁺).

2-Chloro-5-fluoro-N-[4-(1-imidazolylmethyl)phenyl]-4-pyrimidineamine

¹H NMR (DMSO-d₆, 300 MHz): δ 9.99 (s, 1H), 8.29 (d, 1H, J=3.6 Hz), 7.72(s, 1H), 7.62 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.1 Hz), 7.17 (s, 1H),6.88 (s, 1H), 5.15 (s, 2H); LCMS (m/z): 304 (MH⁺).

2-Chloro-5-fluoro-N-[4-(4-pyridinyloxy)phenyl]-4-pyrimidineamine

Prepared by using procedure described in Example 20. ¹H NMR (DMSO-d₆,300 MHz): δ 7.89 (d, 2H, J=7.5 Hz), 7.55 (s, 1H), 7.41 (d, 2H, J=7.8Hz), 7.27 (d, 2H, J=6.9 Hz), 6.16 (d, 2H, J=6.3 Hz), 4.09 (s, 1H); LCMS(m/z): 317 (MH⁺).

2-Chloro-5-fluoro-N-[4-(4-thiomorpholinyl)carbonylphenyl]-4-pyrimidineamine

¹H NMR (DMSO-d₆, 300 MHz): δ 10.11 (s, 1H), 8.35 (d, 1H, J=3.3 Hz), 7.77(d, 2H, J=8.7 Hz), 7.40 (d, 2H, J=8.7 Hz), 3.71 (br s, 4H), 2.64 (br s,4H); LCMS (m/z): 353 (MH⁺).

2-Chloro-5-fluoro-N-[4-(1-methanesulfonyl-4-piperazinyl)carbonylphenyl]-4-pyrimidineamine

¹H NMR (DMSO-d₆, 300 MHz): δ 10.14 (s, 1H), 8.35 (d, 1H, J=2.7 Hz), 7.79(d, 2H, J=8.1 Hz), 7.45 (d, 2H, J=7.8 Hz), 3.59 (br s, 4H), 3.16 (br s,4H), 2.89 (s, 3H); LCMS (m/z): 414 (MH⁺).

2-Chloro-5-fluoro-N-[4-(1-acetyl-4-piperazinyl)carbonylphenyl]-4-pyrimidineamine

¹H NMR (DMSO-d₆, 300 MHz): δ 10.12 (s, 1H), 8.35 (d, 1H, J=3.3 Hz), 7.78(d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=8.7 Hz), 3.47 (br s, 8H), 2.01 (s,3H); LCMS (m/z): 378 (MH⁺).

2-Chloro-5-fluoro-N-[4-(1,1-dioxo-4-thiomorpholinyl)carbonylphenyl]-4-pyrimidineamine

¹H NMR (DMSO-d₆, 300 MHz): δ 10.14 (s, 1H), 8.35 (d, 1H, J=3.3 Hz), 7.79(d, 2H, J=8.4 Hz), 7.51 (d, 2H, J=7.5 Hz), 3.86 (br s, 4H), 3.25 (br s,4H); LCMS (m/z): 385 (MH⁺).

2-Chloro-5-fluoro-N-[4-(2-pyridinyl)-3-methylmethyleneoxyphenyl]-4-pyrimidineamine

¹H NMR (DMSO-d₆, 300 MHz): δ 9.80 (s, 1H), 8.65 (d, 1H, J=5.1 Hz), 8.23(d, 1H, J=4.5 Hz), 8.04 (t, 1H, J=7.8 Hz), 7.69 (d, 1H, J=7.8 Hz), 7.51(t, 1H, J=6.3 Hz), 7.42 (d, 2H, J=9.0 Hz), 7.00 (d, 1H, J=8.4 Hz), 5.27(s, 2H), 2.24 (s, 3H); LCMS (m/z): 345 (MH⁺).

2-Chloro-N4-[3-chloro-4-(2-cyanoethyl)phenyl]-5-fluoro-4-pyrimidineamine

LCMS: 311.35 (MH⁺).

2-Chloro-5-fluoro-N4-(quinolin-8-yl)-4-pyrimidineamine

LCMS: 275.22 (MH⁺).

2-Chloro-5-fluoro-N4-(quinolin-2-yl)-4-pyrimidineamine

LCMS: 275.36 (MH⁺).

2-Chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine

LCMS: 275.28 (MH⁺).

2-Chloro-5-fluoro-N4-(quinolin-3-yl)-4-pyrimidineamine

LCMS: 275.25 (MH⁺).

2-Chloro-5-fluoro-N4-(2-methylquinolin-6-yl)-4-pyrimidineamine

LCMS: 289.38 (MH⁺).

N4-(Benzothiophene-5-yl)-2-chloro-5-fluoro-4-pyrimidineamine

LCMS: 280.26 (MH⁺).

2-Chloro-5-fluoro-N4-(2-methylquinolin-8-yl)-4-pyrimidineamine

LCMS: 289.43 (MH⁺).

2-Chloro-N4-[4-(2-cyanoethyl)phenyl]-5-methyl-4-pyrimidineamine

LCMS: 275.28 (MH⁺).

N4-[(2S,4R)-1-t-Butoxycarbonyl-2-methoxycarbonyl-pyrrolidin-4-yl]-2-chloro-5-fluoro-4-pyrimidineamine

LCMS: 375.01 (MH⁺).

N4-[(2S,4S)-1-t-Butoxycarbonyl-2-methylcarboxylate-pyrrolidine]-2-chloro-5-fluoro-4-pyrimidineamine

LCMS: 375.02 (MH⁺).

2-Chloro-5-fluoro-N4-[(2S,4R)-2-methoxycarbonylpyrrolidin-4-yl]-4-pyrimidineamine

LCMS: 275.36 (MH⁺).

2-Chloro-5-fluoro-N4-[(2S,4S)-2-methoxycarbonylpyrrolidin-4-yl]-4-pyrimidineamine

LCMS: 275.39 (MH⁺).

2-Chloro-N4-[(2S,4R)-1-(2-cyanoacetyl)-2-methoxycarbonylpyrrolidin-4-yl]-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 8.38-8.36 (d, J=7.2 Hz, 1H), 8.13-8.11 (d, J=3.3 Hz,1H), 4.61-4.59 (m, 1H), 4.52-4.47 (m, 1H), 4.06-4.04 (d, J=7.2 Hz, 1H),3.85-3.80 (m, 1H), 3.64 (s, 3H), 3.51-3.46 (m, 1H), 2.43-2.34 (m, 1H),2.20-2.13 (m, 1H), LCMS: 342.01 (MH⁺).

2-Chloro-N4-[(2S,4S)-1-(2-cyanoacetyl)-2-methoxycarbonylpyrrolidin-4-yl]-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 8.20-8.18 (d, J=6.9 Hz, 1H), 8.13 (bs, 1H),4.66-4.61 (m, 1H), 4.37-4.33 (m, 1H), 4.06-4.04 (bs, 2H), 3.90-3.84 (m,1H), 3.63 (s, 3H), 3.47-3.37 (m, 1H), 2.56-2.54 (m, 1H), 2.07-1.98 (m,1H), LCMS: 341.99 (MH⁺).

2-Chloro-N4-[4-(2-cyanoethyl)-3-methylphenyl]-5-fluoro-4-pyrimidineamine

LCMS: 291.05 (MH⁺).

2-Chloro-N4-[4-(2-cyanoethyl)-3-methylphenyl]-5-fluoro-4-pyrimidineamine

LCMS: 291.05 (MH⁺).

Example 232-Chloro-N4-(3-cyanomethyleneoxy-4,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine

A suspension of 3-cyanomethoxy-4,5-dimethoxyaniline (1.5 g),2,4-dichloro-5-fluopyrimidine and 1.3 g of sodium bicarbonate in 70 mL(4:1 EtOH/THF) was stirred overnight at room was diluted with 1 N HClsolution. The precipitate was collected by suction filtration, dried,triturated with ether, recollected by suction filtration and dried toyield 1.3 g 80% of the desired product2-chloro-N4-(3-cyanomethoxy-4,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine.¹H NMR (DMSO-d6): δ 8.18 (d, 1H, J=2.1 Hz), 7.28 (d, 1H, J=4.3 Hz), 7.18(d, 1H, J=4.3 Hz), 5.09 (s, 2H), 3.77 (s, 3H), 3.64 (s, 3H); LCMS:purity 97%; MS (m/e): 339 (MH⁺).

Example 242-Chloro-5-methyl-N4-oxo-benz[1,4]oxazin-6-yl)-4-pyrimidineamine

A mixture of 250 mg of 6-Amino-3-oxo-4H-benz[1,4]oxazine and 460 mg of2,4-Dichloro-5-methylpyrimidine in 15 mL methanol was stirred at RTovernight and was reduced in volume by rotary evaporation. The solutionwas filtered and the filtrate diluted with water and neutralized withsodium bicarbonate. The precipitate was collected by suction filtrationwashed with water and dried on the funnel to yield 75 mg 20% of thedesired product2-Chloro-5-methyl-N4-oxo-benz[1,4]oxazin-6-yl)-4-pyrimidineamine ¹H NMR(DMSO-d6): δ 7.98 (s, 1H), 7.08 (m, 2H), 6.91 (d, 1H J=6 Hz), 4.54 (s,2H), 2.11 (s, 3H) purity 97%; MS (m/e) 291 (MH⁺).

Example 252-Chloro-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-4-pyrimidineamine

A mixture of 1.3 g of 6-Amino-4-methyl-3-oxo-benzo[1,4]thiazine and 3.3g of 2,4-Dichloro-5-methylpyrimidine in 100 mL methanol was stirred atRT overnight and was reduced in volume by rotary evaporation. Thesolution was filtered and the filtrate diluted with water andneutralized with sodium bicarbonate. The precipitate was collected bysuction filtration washed with water and dried on the funnel to yield660 mg 13% of the desired product2-Chloro-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-4-pyrimidineamine¹H NMR (DMSO-d6): δ 8.93 (s, 1H), 8.06 (m, 2H), 7.62 (s, 1H), 7.37 (s,1H), 3.51 (s, 2H), 2.16 (s, 3H) purity 97%; MS (m/e) 321 (MH⁺).

The following compounds were made in a similar fashion to the examples20-25, methods described herein, or methods known to skilled artisans.

2-Chloro-N4-(4-cyanoethylene-2-methylphenyl)-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 9.711 (s, 1H), 8.235-8.219 (d, J=4.8 Hz, 1H),7.251-7.226 (d, J=7.5 Hz, 1H), 7.162-7.122 (m, 2H), 2.852-2.790 (m, 4H),2.130 (s, 3H), LCMS: 291.36 (MH+).

2-Chloro-N4-(4-cyanoethylene-3-methoxyphenyl)-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 9.959 (s, 1H), 8.305-8.293 (d, J=3.6 Hz, 1H), 7.410(s, 1H), 7.285-7.262 (d, J=6.9 Hz, 1H), 7.192-7.164 (d, J=8.4 Hz, 1H),3.784 (s, 3H), 2.808-2.726 (m, 4H), LCMS: 307.04 (MH+).

2-Chloro-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 11.809 (s, 1H), 8.442-8.432 (d, J=3.0 Hz, 1H),7.665-7.649 (d, J=4.8 Hz, 1H), 7.017-7.001 (d, J=4.8 Hz, 1H), 3.793 (s,3H), LCMS: 288.25 (MH+).

2-Chloro-5-fluoro-N4-(2-hydroxy-4-methylquinolin-6-yl)-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 11.599 (s, 1H), 10.077 (s, 1H), 8.291-8.280 (d,J=3.3 Hz, 1H), 8.064 (s, 1H), 7.766-7.736 (d, J=9 Hz, 1H), 7.295-7.266(d, J=8.7 Hz, 1H), 6.410 (s, 1H), 2.389 (s, 3H).

2-Chloro-N4-(4-cyanoethylene-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 10.223 (s, 1H), 8.372-8.360 (d, J=3.6 Hz, 1H), 8.138(s, 1H), 8.004-7.975 (d, J=8.7 Hz, 1H), 7.599-7.571 (d, J=8.4 Hz, 1H),3.047-2.999 (t, 2H), 2.885-2.837 (t, 2H), LCMS: 344.93 (MH+).

N4-[4-(2-Carboxyethylene)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 12.075 (s, 1H), 9.908 (s, 1H), 8.271-8.260 (d, J=3.3Hz, 1H), 7.548-7.520 (d, J=8.4 Hz, 2H), 7.221-7.193 (d, J=8.4 Hz, 2H),2.818-2.767 (t, 2H), 2.549-2.497 (t, 2H).

N4-[4-(2-Aminocarboxylethylene)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 8.269-8.257 (d, J=3.6 Hz, 1H), 7.540-7.512 (d, J=8.4Hz, 2H), 7.266 (s, 1H), 7.197-7.169 (d, J=8.4 Hz, 2H), 6.740 (s, 1H),2.796-2.745 (t, 2H), 2.365-2.313 (t, 2H), LCMS: 295.30 (MH+).

2-Chloro-N4-[3,4-dihydro-(1H)-quinolin-2-one-6-yl]-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 9.963 (s, 1H), 7.919 (s, 1H), 7.260-7.215 (m, 2H),6.766-6.739 (d, J=8.1 Hz, 1H), 2.845-2.796 (t, 2H), 2.442-2.392 (t, 2H),LCMS: 293.01 (MH+).

2-Chloro-N4-(2-N,N′-dimethylamino-quinolin-6-yl)-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 10.015 (s, 1H), 8.273-8.261 (d, J=3.6 Hz, 1H),7.955-7.925 (m, 2H), 7.705 (s, 1H), 7.532-7.502 (d, J=9 Hz, 1H),7.077-7.047 (d, J=9.0 Hz, 1H), 3.138 (s, 6H).

N4-[(4R)-1-tert-Butoxycarbonyl-pyrrolidin-4-yl]-2-chloro-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 8.330-8.309 (d, J=6.3 Hz, 1H), 8.093-8.081 (d, J=3.6Hz, 1H), 4.462-4.444 (m, 1H), 3.587-3.528 (m, 1H), 3.436-3.378 (m, 1H),3.208-3.154 (m, 1H), 2.138-2.095 (m, 1H), 1.958-1.914 (m, 1H), 1.395 (s,9H).

2-Chloro-N4-[(4R)-1-(2-cyanoacetyl)-pyrrolidin-4-yl]-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 8.320 (s, 1H), 8.113-8.092 (d, J=6.3 Hz, 1H),4.543-4.001 (m, 1H), 3.908 (s, 2H), 3.718-3.543 (m, 1H), 3.520-3.299 (m,3H), 2.208-1.979 (m, 2H), LCMS: 284.29 (MH+).

N4-(2-cyanoethylene-benzothiophene-5-yl)-2-chloro-5-fluoro-4-pyrimidineamine

¹H NMR (DMSO-d₆): δ 11.104 (s, 1H), 8.326-8.308 (d, J=5.4 Hz, 1H),7.963-7.934 (d, J=8.7 Hz, 1H), 7.813 (s, 1H), 7.391-7.355 (d, J=9 Hz,1H), 7.313 (s, 1H), 3.248-3.202 (t, 2H), 2.969-2.922 (t, 2H).

Example 26

I-230:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(59, X═H)

A mixture of2-chloro-5-fluoro-N-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(54, X═H) (100 mg, 0.298 mmol), 3-aminobenzenesulfonamide (51.2 mg,0.298 mmol) and trifluoroacetic acid (TFA) (2 drops) in MeOH (2 mL) werereacted in sealed reaction vial at 100° C. for 24 hours. The product waspurified by column chromatography [silica gel column, eluted withCH₂Cl₂: 2M NH₃ in MeOH (1-3%)] to provide ofN2-(3-aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(59, X═H). This reaction also works well in absence of trifluoroaceticacid. ¹H NMR (DMSO-d₆): δ 9.46 (s, 1H), 9.28 (s, 1H), 8.06 (d, 2H, J=1.2Hz), 7.93 (m, 1H), 7.69 (d, 2H, J=9.3 Hz), 7.33 (m, 2H), 7.26 (s, 2H),6.98 (d, 2H, J=9.0 Hz), 6.32 (s, 1H), 5.13 (s, 2H), 2.40 (s, 3H); LCMS(m/z): 471 (MH⁺).

The following compounds were made in a similar fashion to the example26.

I-219:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (CD₃OD): δ 8.08 (d, J=2.7 Hz, 1H), 7.87 (d, J=3.6 Hz, 1H), 7.72(dd, J=2.4 and 8.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.1 Hz,1H), 6.99 (d, J=8.7 Hz, 2H), 6.25 (s, 1H), 5.13 (s, 2H), 2.60 (s, 3H),2.44 (s, 3H); LCMS: purity: 94%; MS (m/z): 485(MH⁺).

I-220:N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.59 (s, 1H), 9.31 (s, 1H), 8.27 (d, J=1.8 Hz, 1H),8.08 (d, J=3.6 Hz, 1H), 8.04-7.98 (m, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.46(s, 2H), 7.40 (d, J=8.7 Hz, 1H), 6.99 (d, J=9.0 Hz, 2H), 6.33 (s, 1H),5.13 (s, 2H), 2.41 (s, 3H); LCMS: purity: 89%; MS (m/z): 506(MH⁺).

I-221:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-chloro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.44 (s, 1H), 9.36 (s, 1H), 8.08 (d, J=3.6 Hz, 1H),8.06-8.02 (m, 1H), 7.91-7.85 (m, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.74 (dd,J=2.7 and 9.0 Hz, 1H), 7.26-7.13 (m, 4H), 6.33 (s, 1H), 5.22 (s, 2H),2.59 (s, 3H), 2.41 (s, 3H); LCMS: purity: 99%; MS (m/z): 520(MH⁺).

I-222:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.46 (s, 1H), 9.39 (s, 1H), 8.13-8.06 (m, 2H),7.93-7.84 (m, 2H), 7.52 (d, J=9.3 Hz, 1H), 7.28-7.22 (m, 2H), 7.18 (d,J=8.4 Hz, 1H), 6.34 (s, 1H), 5.20 (s, 2H), 2.50 (s, 3H), 2.41 (s, 3H);LCMS: purity: 95%; MS (m/z): 503(MH⁺).

I-233:N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.42 (s, 1H), 9.27 (s, 1H), 8.05 (d, 2H, J=3.3 Hz),7.95 (m, 1H), 7.66 (d, 2H, J=9.0 Hz), 7.54 (s, 2H), 7.21 (t, 1H, J=9.3Hz), 6.98 (d, 2H, J=8.7 Hz), 6.32 (s, 1H), 5.12 (s, 2H), 2.40 (s, 3H);LCMS (m/z): 489 (MH⁺).

I-234:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.33 (s, 1H), 9.15 (s, 1H), 8.05 (s, 1H), 8.02 (d,1H, J=3.3 Hz), 7.90 (d, 1H, J=8.7 Hz), 7.52 (m, 2H), 7.22 (s, 2H), 7.12(d, 1H, J=8.4 Hz), 6.98 (d, 1H, J=8.7 Hz), 6.33 (s, 1H), 5.13 (s, 2H),2.49 (s, 3H), 2.41 (s, 3H), 2.16 (s, 3H); LCMS (m/z): 499 (MH⁺).

I-235:5-Fluoro-N2-[3-(N-methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.42 (s, 1H), 9.31 (s, 1H), 8.11 (d, 1H, J=3.0 Hz),8.06 (s, 1H), 7.99 (d, 1H, J=8.4 Hz), 7.75 (d, 2H, J=8.4 Hz), 7.38 (q,1H, J=4.8 Hz), 7.24 (d, 1H, J=8.4 Hz), 7.04 (d, 2H, J=8.7 Hz), 6.38 (s,1H), 5.18 (s, 2H), 2.55 (d, 3H, J=1.8 Hz), 2.52 (s, 3H), 2.46 (s, 3H);LCMS (m/z): 499 (MH⁺).

I-237:N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[3methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.41 (s, 1H), 9.19 (s, 1H), 8.01 (m, 3H), 7.46 (m,3H), 7.18 (t, 1H, J=9.6 Hz), 7.00 (d, 2H, J=9.0 Hz), 6.34 (s, 1H), 5.14(s, 2H), 2.41 (s, 3H), 2.17 (s, 3H); LCMS (m/z): 503 (MH⁺).

I-223:N2-(3-Aminosulfonyl-5-chloro-4-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.71 (s, 1H), 9.50 (s, 1H), 8.25 (d, J=2.4 Hz, 1H),8.14 (d, J=3.9 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.79 (dd, J=2.7 and 13.5Hz, 1H), 7.53-7.40 (m, 3H), 7.20 (t, J=9.3 Hz, 1H), 6.32 (s, 1H), 5.18(s, 2H), 3.51 (s, 3H), 2.41 (s, 3H); LCMS: purity: 93%; MS (m/z):538(MH⁺).

I-224:N2-(3-Aminosulfonyl-4-fluoro-5-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.57 (s, 1H), 8.12 (d, J=4.2 Hz, 1H), 7.88-7.82 (m,1H), 7.81-7.73 (m, 2H), 7.49-7.42 (m, 1H), 7.20 (t, J=9.0 Hz, 1H), 6.32(s, 1H), 5.18 (s, 2H), 2.41 (s, 3H), 2.19 (s, 3H); LCMS: purity: 94%; MS(m/z): 521(MH⁺).

I-238:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.45 (s, 1H), 9.19 (s, 1H), 8.05 (d, 1H, J=3.6 Hz),8.02-7.96 (m, 2H), 7.51 (m, 2H), 7.31 (d, 2H, J=4.8 Hz), 7.24 (s, 2H),6.99 (d, 1H, J=8.4 Hz), 6.33 (s, 1H), 5.13 (s, 2H), 2.41 (s, 3H), 2.17(s, 3H); LCMS (m/z): 485 (MH⁺).

I-216:N2-(3-Aminosulfonyl-5-chloro-4-methylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 96%, MS (m/e): 520 (MH+).

I-217:N2-(3-Aminosulfonyl-4-fluoro-5-methylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%, MS (m/e): 504 (MH+).

V-1:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[2-(5-methylisoxazol-3-yl)methyleneoxypyridin-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.33 (s, 1H), 9.21 (s, 1H), 8.14 (d, J=2.4 Hz, 1H),8.05 (s, J=2.4 Hz, 2H), 7.81 (dd, J=2.4 and 8.7 Hz, 1H), 7.71 (dd, J=2.7and 9.6 Hz, 1H), 7.24 (s, 2H), 7.12 (d, J=8.4 Hz, 1H), 6.46 (d, J=9.6Hz, 1H), 6.11 (s, 1H), 5.13 (s, 2H), 2.48 (s, 3H), 2.34 (s, 3H); LCMS:purity: 87%; MS (m/z): 486(MH⁺).

I-240:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.56 (s, 1H), 9.27 (s, 1H), 8.09 (d, 1H,J=3.6 Hz), 7.78 (d, 2H, J=8.7 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.51 (s, 1H),7.43 (d, 1H, J=8.7 Hz), 7.12 (s, 2H), 7.02 (d, 1H, J=8.4 Hz), 6.35 (s,1H), 5.14 (s, 2H), 2.41 (s, 3H), 2.19 (s, 3H); LCMS (m/z): 485 (MH⁺).

I-214:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.45 (s, 1H), 9.37 (s, 1H), 8.14-8.05 (m, 2H), 7.93(d, J=9.0 Hz, 1H), 7.53-7.49 (m, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.27-7.20(m, 3H), 7.16 (d, J=8.1 Hz, 1H), 6.73 (d, J=9.3 Hz, 1H), 6.31 (s, 1H),5.12 (s, 2H), 2.49 (s, 3H), 2.40 (s, 3H); LCMS: purity: 96%; MS (m/z):485(MH⁺).

I-206:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-morpholinoethyloxy)phenyl-2,4-pyrimidinediamine

LCMS: purity: 93%; MS (m/z): 489(MH⁺).

I-207:5-Fluoro-N2-(3-morpholinosulfonylphenyl)-N4-[4-(2-morpholinoethyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.56 (s, 1H), 9.32 (s, 1H), 8.10 (d, 1H, J=3.9 Hz),7.80 (d, 2H, J=8.1 Hz), 7.60 (3H, dd, J=2.4 Hz and 2.1 Hz), 7.12 (s,2H), 6.96 (d, 2H, J=8.7 Hz), 3.58 (m, 3H), 3.32 (m, 8H), 3.30 (m, 8H),2.70 (t, 2H, J=5.7 Hz); LCMS: purity: 93%; MS (m/z): 559(MH⁺).

I-208:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholinocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.68 (s, 1H), 9.53 (s, 1H), 8.15 (d, 1H, J=3.9 Hz),8.10 (s, 1H), 7.92 (m, 1H), 7.46 (s, 1H), 7.40 (m, 2H), 7.23 (m, 2H),7.10 (d, 1H, J=8.4 Hz), 4.82 (s, 2H), 3.75 (bs, 4H), 3.50 (bs, 4H), 2.16(s, 3H); LCMS: purity: 90%; MS (m/z): 503(MH⁺).

I-209:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholinocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.85 (s, 1H), 9.64 (s, 1H), 8.18 (d, 1H, J=3.6 Hz),7.80 (d, 2H, J=8.4 Hz), 7.65 (d, 2H, J=8.7 Hz), 7.38 (s, 1H), 7.16 (m,2H), 4.80 (s, 2H), 3.51 (s, 4H), 3.43 (s, 4H), 2.18 (s, 3H); LCMS:purity: 88%; MS (m/z): 517 (MH⁺).

I-203:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholinoethyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.48 (s, 1H), 9.26 (s, 1H), 8.10 (d, 1H, J=3.9 Hz),7.97 (d, 1H, J=6.9 Hz), 7.36 (m, 3H), 7.25 (s, 2H), 7.09 (s, 1H), 4.03(m, 2H), 3.55 (bs, 4H), 3.31 (bs, 4H), 2.71 (m, 2H), 2.13 (s, 3H); LCMS:purity: 87%; MS (m/z): 503(MH⁺).

VII-51:N2-(3-Aminosulfonylphenyl)-N4-[2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 11.11 (s, 1H), 9.63 (s, 1H), 9.48 (s, 1H), 8.42 (t,1H, J=2.1 Hz), 8.13 (t, 2H, J=3.3 Hz), 7.95 (d, 1H, J=7.8 Hz), 7.87 (d,1H, J=2.1 Hz), 7.41 (m, 2H), 7.25 (s, 1H), 1.45 (s, 6H); LCMS: purity:92%; MS (m/z): 460(MH⁺).

VII-52:N2-(4-Aminosulfonylphenyl)-N4-[2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 11.14 (s, 1H), 9.70 (s, 1H), 9.53 (s, 1H), 8.16 (s,1H), 7.81 (d, 2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.11 (s, 2H), 1.45(s, 6H); LCMS: purity: 95%; MS (m/z): 460(MH⁺).

VII-42:N2-(3-Aminosulfonylphenyl)-N4-[2,2,4-trimethyl-3-oxo-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.64 (s, 1H), 8.62 (s, 1H), 8.15 (d, 2H, J=3.9 Hz),7.93 (t, 2H, J=7.2 Hz), 7.37 (m, 3H), 2.43 (s, 3H), 1.45 (s, 6H); LCMS:purity: 94%; MS (m/z): 474(MH⁺).

VII-43:N2-(4-Aminosulfonylphenyl)-N4-[2,2,4-trimethyl-3-oxo-5-pyrid[1,4]oxazin-5-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 11.14 (s, 1H), 9.70 (s, 1H), 9.53 (s, 1H), 8.16 (s,1H), 7.81 (d, 2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.11 (s, 2H), 2.43(s, 3H), 1.45 (s, 6H); LCMS: purity: 90%; MS (m/z): 474 (MH⁺).

I-204:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholinoethyloxy)phenyl]2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.38 (s, 1H), 9.22 (s, 1H), 8.09 (d, 1H, J=1.5 Hz),7.92 (d, 1H, J=2.4 Hz), 7.40 (d, 2H, J=8.1 Hz), 7.26 (s, 2H), 7.15 (s,1H), 4.10 (t, 2H, J=5.7 Hz), 3.54 (bs, 4H), 2.69 (bs, 2H), 2.49 (s, 6H),2.12 (s, 4H).

VI-111:N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-[4-(2-methoxyethyleneoxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 94%; MS (m/z): 468(MH⁺).

V-14:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[2,2-dimethyl-3-oxo-4-cyanomethyl-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.65 (s, 1H), 8.15 (d, 1H, J=3.6 Hz), 8.09 (s, 1H),8.01 (s, 1H), 7.91 (m, 2H), 5.10 (s, 2H), 2.07 (s, 3H), 1.50 (s, 6H);LCMS: purity: 96%; MS (m/z): 513 (MH⁺).

V-15:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-[2,2-dimethyl-3-oxo-4-cyanomethyl-5-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.66 (d, 1H, J=2.4 Hz), 8.27 (d, 1H, J=3.6 Hz), 8.19(d, 1H, J=3.6 Hz), 8.10 (m, 1H), 7.48 (d, 2H, J=1.8 Hz), 5.10 (s, 2H),1.52 (s, 6H); LCMS: purity: 96%; MS (m/z): 533 (MH⁺).

VI-112:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-methoxyethyleneoxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 91%; MS (m/z): 448(MH⁺).

I-205:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-morpholinoethyloxy)phenyl)-2,4-pyrimidinediamine

LCMS: purity: 87%; MS (m/z): 489 (MH⁺).

VII-26: RacemicN2-(3-Aminosulfonyl-4-methylphenyl)-N4-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.17 (d, 1H, J=4.8 Hz), 7.86 (s, 1H), 7.82 (d, 1H,J=2.1 Hz), 7.50 (s, 1H), 7.27 (t, 2H, J=8.4 Hz), 6.79 (d, 1H, J=8.4 Hz),5.67 (t, 2H, J=8.1 Hz), 2.88 (s, 6H), 2.49 (s, 3H); LCMS: purity: 90%;MS (m/z): 487 (MH⁺).

VII-27: RacemicN2-(3-Aminosulfonyl-4-chlorophenyl)-N4-[2-(N,N-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 7.95 (dd, 2H, J=2.7 Hz and 2.4 Hz), 7.30 (dd, 3H,J=2.4 Hz and 2.4 Hz), 6.80 (d, 2H, J=8.7 Hz), 5.67 (t, 2H, J=7.5 Hz),2.88 (s, 6H); LCMS: purity: 90%; MS (m/z): 507 (MH⁺).

IX-9:N4-[3-(Aminocarbonyl)-1H-indol-6-yl]-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 7.83 (d, 2H, J=7.8 Hz), 7.41 (s, 2H), 7.26 (s, 2H),7.10 (d, 2H, J=8.4 Hz), 2.45 (s, 3H); LCMS: purity: 96%; MS (m/z): 456(MH⁺).

IX-10:N4-[3-(Aminocarbonyl)-1H-indol-6-yl]-N2-(3-aminosulfonyl-4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.18 (s, 1H), 8.12 (s, 1H), 8.03 (m, 2H), 7.44 (m,3H), 7.15 (d, 1H, J=9.0 Hz); LCMS: purity: 87%; MS (m/z): 476 (MH⁺).

IX-11:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-cyanomethyl-1H-indol-6-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 7.95 (d, 1H, J=8.4 Hz), 7.64 (s, 1H), 7.55 (d, 1H,J=8.4 Hz), 7.41 (m, 1H), 7.29 (s, 1H), 7.20 (s, 2H), 7.06 (d, 1H, J=8.7Hz), 4.04 (s, 2H), 2.45 (s, 3H); LCMS: purity: 96%; MS (m/z): 452 (MH⁺).

IX-12:N2-(3-Aminosulfonylphenyl)-N4-(3-cyanomethyl-1H-indol-6-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.08 (t, 1H, J=3.3 Hz), 8.01 (d, 1H, J=3.0 Hz), 7.65(s, 1H), 7.55 (d, 2H, J=8.4 Hz), 7.43 (d, 1H, J=8.1 Hz), 7.26 (m, 3H),4.04 (s, 2H); LCMS: purity: 93%; MS (m/z): 438 (MH⁺).

IX-13:N2-(3-Aminosulfonylphenyl)-N4-(3-cyanomethyl-1H-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.06 (d, 1H, J=3.9 Hz), 7.96 (d, 1H, J=8.4 Hz), 7.87(s, 1H), 7.35 (m, 5H), 4.02 (s, 2H); LCMS: purity: 96%; MS (m/z): 438(MH⁺).

IX-14:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-cyanomethyl-1H-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.07 (s, 1H), 8.02 (d, 1H, J=3.9 Hz), 7.87 (s, 2H),7.41 (s, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 7.20 (s, 1H), 4.01 (s, 2H),2.42 (s, 3H); LCMS: purity: 97%; MS (m/z): 452 (MH⁺).

I-244:N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.45 (s, 1H), 9.20 (s, 1H), 8.05 (m, 3H),7.50 (m, 2H), 7.34 (t, 1H, J=7.5 Hz), 7.26 (d, 2H, J=7.8 Hz), 7.00 (d,1H, J=9.3 Hz), 6.33 (s, 1H), 5.13 (s, 2H), 2.79 (t, 2H, J=7.8 Hz), 2.41(s, 3H), 2.38 (m, 6H), 2.17 (s, 3H), 0.85 (t, 6H, J=6.9 Hz); LCMS (m/z):584 (MH⁺).

I-245:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.62 (s, 1H), 9.28 (s, 1H), 8.09 (d, 1H, J=3.3 Hz),7.80 (d, 2H, J=8.7 Hz), 7.55 (d, 2H, J=8.7 Hz), 7.52 (d, 1H, J=2.7 Hz),7.40 (dd, 1H, J=2.4 and 8.5 Hz), 7.17 (br s, 1H), 7.01 (d, 1H, J=8.7Hz), 6.34 (s, 1H), 5.13 (s, 2H), 2.71 (t, 2H, J=7.8 Hz), 2.41 (s, 3H),2.38 (m, 6H), 2.18 (s, 3H), 0.83 (t, 6H, J=6.9 Hz); LCMS (m/z): 584(MH⁺).

I-239:5-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[3-methyl-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.34 (s, 1H), 9.16 (s, 1H), 8.03 (d, 1H, J=3.9 Hz),7.96 (m, 2H), 7.50 (m, 2H), 7.32 (q, 1H, J=4.5 Hz), 7.15 (d, 1H, J=9.0Hz), 6.99 (d, 1H, J=8.4 Hz), 6.33 (s, 1H), 5.13 (s, 2H), 2.45 (s, 3H),2.41 (d, 3H, J=3.3 Hz), 2.40 (s, 3H), 2.16 (s, 3H); LCMS (m/z): 513(MH⁺).

I-241:N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.45 (s, 1H), 9.28 (s, 1H), 8.05 (m, 2H), 7.98 (d,1H, J=8.4 Hz), 7.67 (d, 2H, J=9 Hz), 7.36 (t, 1H, J=8.1 Hz), 7.26 (d,2H, J=8.1 Hz), 6.98 (d, 2H, J=9.0 Hz), 6.32 (s, 1H), 5.12 (s, 2H), 2.79(t, 2H, J=8.1 Hz), 2.40 (s, 3H), 2.37 (m, 6H), 0.84 (t, 6H, J=6.9 Hz);LCMS (m/z): 570 (MH⁺).

I-246:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.60 (s, 1H), 9.34 (s, 1H), 8.10 (d, 1H, J=3.9 Hz),7.81 (d, 2H, J=9.0 Hz), 7.63 (d, 2H, J=9.0 Hz), 7.57 (d, 2H, J=8.7 Hz),7.15 (br s, 1H), 7.01 (d, 2H, J=9.3 Hz), 6.32 (s, 1H), 5.12 (s, 2H),2.73 (t, 2H, J=7.5 Hz), 2.40 (s, 3H), 2.36 (m, 6H), 0.84 (t, 6H, J=6.9Hz); LCMS (m/z): 570 (MH⁺).

I-252:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(60)

¹H NMR (DMSO-d6): δ 9.51 (s, 1H), 9.39 (s, 1H), 8.13 (d, 1H, J=2.1 Hz),8.09 (s, 1H), 7.98 (d, 1H, J=6.9 Hz), 7.51 (br s, 2H), 7.41-7.25 (m,4H), 6.73 (d, 2H, J=7.5 Hz), 5.45 (s, 2H), 2.35 (s, 3H); LCMS (m/z): 472(MH⁺).

I-253:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.62 (s, 1H), 9.46 (s, 1H), 8.16 (d, 1H,J=2.1 Hz), 7.82 (d, 2H, J=7.5 Hz), 7.62 (d, 2H, J=7.2 Hz), 7.49 (d, 1H,J=8.1 Hz), 7.43 (s, 1H), 7.26 (t, 1H, J=8.1 Hz), 7.11 (br s, 2H), 6.76(d, 1H, J=8.1 Hz), 5.46 (s, 2H), 2.34 (s, 3H); LCMS (m/z): 472 (MH⁺).

I-231:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.62 (s, 1H), 9.46 (s, 1H), 8.16 (d, 1H, J=2.1 Hz),7.82 (d, 2H, J=7.5 Hz), 7.62 (d, 2H, J=7.2 Hz), 7.49 (d, 1H, J=8.1 Hz),7.43 (s, 1H), 7.26 (t, 1H, J=8.1 Hz), 7.11 (br s, 2H), 6.76 (d, 1H,J=8.1 Hz), 5.46 (s, 2H), 2.34 (s, 3H); LCMS (m/z): 472 (MH⁺).

I-259:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.35 (s, 1H), 9.26 (s, 1H), 8.08 (s, 1H), 8.04 (d,1H, J=3.3 Hz), 7.86 (d, 1H, J=7.5 Hz), 7.71 (d, 2H, J=8.7 Hz), 7.22 (s,2H), 7.13 (d, 1H, J=8.4 Hz), 6.99 (d, 2H, J=9.0 Hz), 5.45 (s, 2H), 2.49(s, 3H), 2.36 (s, 3H); LCMS (m/z): 486 (MH⁺).

I-258:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.47 (s, 1H), 9.31 (s, 1H), 8.07 (d, 2H, J=3.0 Hz),7.90 (d, 1H, J=6.6 Hz), 7.70 (d, 2H, J=8.7 Hz), 7.33 (m, 2H), 7.25 (s,2H), 7.00 (d, 2H, J=9.0 Hz), 5.46 (s, 2H), 2.49 (s, 3H), 2.36 (s, 3H);LCMS (m/z): 472 (MH⁺).

I-254:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.41 (s, 1H), 9.35 (s, 1H), 8.09 (m, 2H), 7.92 (dd,2H, J=2.1 and 8.1 Hz), 7.51 (m, 2H), 7.22 (m, 5H), 6.74 (dd, 2H, J=2.1and 8.2 Hz), 5.45 (s, 2H), 2.45 (s, 3H); LCMS (m/z): 486 (MH⁺).

III-14:N2-(3-aminosulfonylphenyl)-N4-[4-(cyanoethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.52 (s, 1H), 9.37 (s, 1H), 8.11-8.10 (d, J=3 Hz,2H), 7.98-7.95 (d, J=9.0 Hz, 1H), 7.77-7.74 (d, J=9.0 Hz, 2H), 7.39-7.32(m, 2H), 7.26 (s, 2H), 7.23 (s, 2H), 2.86-2.79 (m, 4H); LCMS (m/z):412.97 (MH⁺).

III-15:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(cyanoethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.40 (s, 1H), 9.32 (s, 1H), 8.10-8.06 (m, 2H), 7.92(br s, 1H), 7.25-7.17 (m, 5H), 2.48 (s, 3H); LCMS (m/z): 427.01 (MH⁺).

III-16:N2-(3-Aminosulfonyl-4-fluorophenyl)-N4-[4-(cyanoethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.47 (s, 1H), 9.36 (s, 1H), 8.09-8.08 (d, J=3.0 Hz,1H) 8.06-8.04 (m, 1H), 8.02-7.98 (m, 1H), 7.75-7.72 (d, J=9.0 Hz, 2H),7.54 (s, 2H), 7.28-7.22 (m, 3H), 2.86-2.81 (m, 4H); LCMS: (m/z): 430.98(MH⁺).

III-106:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)ethylenephenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.50 (s, 1H), 9.33 (s, 1H), 8.10 (br s, 2H),7.97-7.94 (bd, J=9.0 Hz, 1H), 7.73-7.70 (d, J=9.0 Hz, 2H), 7.35 (m, 2H),7.25 (s, 2H), 7.21-7.18 (d, J=9.0 Hz, 2H), 3.23-3.19 (m, 2H), 3.06-3.01(m, 2H), 2.30 (s, 3H); LCMS (m/z): 469.88 (MH⁺).

I-267:N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)ethylenephenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.411 (s, 1H), 9.30 (br s, 1H), 8.07-8.06 (d, J=3Hz, 1H), 8.01 (m, 1H), 7.95 (m, 1H), 7.71-7.68 (d, J=9.0 Hz, 2H),7.21-7.18 (d, J=9.0 Hz, 2H), 3.23-3.18 (m, 2H), 3.05-3.00 (m, 2H), 2.29(s, 3H); LCMS (m/z): 488.41 (MH⁺).

I-266:N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.52 (s, 1H), 9.44 (s, 1H), 8.08-8.07 (d, J=3 Hz,1H), 8.01-7.99 (m, 1H), 7.95-7.92 (m, 1H), 7.68-7.65 (d, J=9.0 Hz, 2H),7.55 (s, 2H), 7.28-7.20 (m, 1H), 7.03-7.00 (d, J=9.0 Hz, 2H), 5.46 (s,2H), 2.36 (s, 3H); LCMS (m/z): 490.36 (MH⁺).

I-260:5-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.35 (s, 1H), 9.27 (s, 1H), 8.05 (d, 1H, J=3.6 Hz),8.00 (d, 1H, J=2.4 Hz), 7.92 (dd, 1H, J=2.4 and 8.2 Hz), 7.71 (d, 2H,J=9.0 Hz), 7.31 (q, 1H, J=4.8 Hz), 7.18 (d, 1H, J=8.1 Hz), 7.00 (d, 2H,J=9.3 Hz), 5.45 (s, 2H), 2.45 (s, 3H), 2.41 (d, 3H, J=4.8 Hz), 2.35 (s,3H), 2.46 (s, 3H); LCMS (m/z): 500 (MH⁺).

I-255:5-Fluoro-N2-[3-(N-methylaminosulfonyl)-4-methylphenyl]-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.41 (s, 1H), 9.36 (s, 1H), 8.11 (d, 1H, J=3.6 Hz),7.99 (m, 2H), 7.50 (m, 2H), 7.32 (q, 1H, J=4.8 Hz), 7.22 (t, 2H, J=8.1Hz), 6.72 (dd, 1H, J=2.4 and 8.1 Hz), 5.43 (s, 2H), 2.44 (s, 3H), 2.41(d, 3H, J=4.5 Hz), 2.35 (s, 3H); LCMS (m/z): 500 (MH⁺).

I-261:N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.54 (s, 1H), 9.41 (s, 1H), 8.14 (d, 1H, J=3.3 Hz),8.07 (s, 1H), 8.03 (d, 1H, J=8.4 Hz), 7.50 (m, 2H), 7.41 (t, 1H, J=8.1Hz), 7.34 (br s, 1H), 7.25 (d, 2H, J=8.1 Hz), 6.74 (d, 1H, J=6.9 Hz),5.45 (s, 2H), 2.79 (t, 2H, J=7.5 Hz), 2.35 (m, 9H), 0.84 (t, 6H, J=6.9Hz); LCMS (m/z): 571 (MH⁺).

I-256:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.68 (s, 1H), 9.47 (s, 1H), 8.17 (d, 1H, J=3.6 Hz),7.85 (d, 2H, J=9.0 Hz), 7.60 (d, 2H, J=9.0 Hz), 7.44 (m, 2H), 7.27 (t,2H, J=8.4 Hz), 6.76 (dd, 1H, J=2.4 and 8.1 Hz), 5.46 (s, 2H), 2.74 (t,2H, J=7.8 Hz), 2.41 (m, 6H), 2.34 (s, 3H), 0.86 (t, 6H, J=7.2 Hz); LCMS(m/z): 571 (MH⁺).

I-262:N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆): δ 9.47 (s, 1H), 9.31 (s, 1H), 8.08 (d, 1H, J=3.9 Hz),8.05 (s, 1H), 7.98 (d, 1H, J=8.4 Hz), 7.70 (d, 2H, J=9.0 Hz), 7.37 (t,2H, J=7.8 Hz), 7.26 (d, 1H, J=8.1 Hz), 5.46 (s, 2H), 2.79 (t, 2H, J=7.5Hz), 2.36 (m, 9H), 0.85 (t, 6H, J=6.9 Hz); LCMS (m/z): 571 (MH⁺).

VIII-1:5-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(sacchrin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 10.07 (s, 1H), 9.44 (s, 1H), 8.46 (s, 1H),8.18 (d, 1H, J=3.6 Hz), 7.84 (d, 1H, J=8.4 Hz), 7.70 (d, 1H, J=8.7 Hz),7.60 (d, 2H, J=9.3 Hz), 7.05 (d, 2H, J=9.0 Hz), 6.45 (br s, 1H), 6.33(s, 1H), 5.15 (s, 2H), 2.41 (s, 3H); LCMS (m/z): 497 (MH⁺).

I-198:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(1,3-dimethyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.33 (s, 1H), 9.22 (s, 1H), 8.09 (d, J=2.4 Hz, 1H),8.03 (d, J=3.6 Hz, 1H), 7.85 (dd, J=2.1 and 8.4 Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.21 (s, 2H), 7.14 (d, J=8.1 Hz, 1H), 6.99 (d, J=8.7 Hz, 2H),6.12 (s, 1H), 5.08 (s, 2H), 3.74 (s, 3H), 2.48 (s, 3H), 2.10 (s, 3H);LCMS: purity: 98%; MS (m/z): 498(MH⁺).

I-199:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(1-benzyl-3-methyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.39 (s, 1H), 9.29 (s, 1H), 8.07 (d, J=2.1 Hz, 1H),8.04 (d, J=3.9 Hz, 1H), 7.84 (dd, J=2.1 and 8.4 Hz, 1H), 7.64 (d, J=9.0Hz, 2H), 7.33-7.22 (m, 5H), 7.18-7.11 (m, 3H), 6.90 (d, J=9.0 Hz, 2H),6.19 (s, 1H), 5.28 (s, 2H), 5.06 (s, 2H), 2.49 (s, 3H), 2.13 (s, 3H);LCMS: purity: 98%; MS (m/z): 575(MH⁺).

I-197:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-methyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

A methanol (1.0 mL) suspension ofN2-(3-aminosulfonyl-4-methylphenyl)-N4-[4-(1-benzyl-3-methyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine(63, Y=benzyl, 50 mg, 0.087 mmol), 10% Pd/C (20 mg), and 4N HCl (30 μL,0.12 mmol) was degassed under vacuum, back-filled with hydrogen, andstirred for 24 h under a balloon of hydrogen at room temperature. Thereaction mixture was then filtered through Celite, and the filter cakewas washed with methanol (10 mL). Removal of methanol under vacuum gave43 mg ofN2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-methyl-(1H)-pyrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamineas an off-white solid (63, Y═H). ¹H NMR (DMSO-d₆): δ 12.45 (s, 1H), 9.33(s, 1H), 9.21 (s, 1H), 8.09 (d, J=1.5 Hz, 1H), 8.02 (d, J=3.9 Hz, 1H),7.86 (dd, J=2.1 and 8.1 Hz, 1H), 7.66 (d, J=9.0 Hz, 2H), 7.29-7.19 (m,2H), 7.14 (d, J=8.1 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 6.05 (s, 1H), 4.95(s, 2H), 2.49 (s, 3H), 2.20 (s, 3H); LCMS: purity: 95%; MS (m/z): 484(MH⁺).

Example 27

I-16:N2-(4-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

4-Nitrophenol (10 g), bromoacetamide (10 g) and K₂CO₃ (15 g) weresuspended in acetone (30 mL). The yellow solution was stirred at rt for3 d. The reaction mixture was diluted with water and acetone was removedunder reduced pressure. The light-yellow precipitate was collected byfiltration, washed with water and dried to giveO-aminocarbonylmethyl-4-nitrophenol (11.5 g) as a beige solid.

O-Aminocarbonylmethyl-4-nitrophenol (5 g) was dissolved in methanol (50mL) and to the solution was added 10% Pd—C (500 mg). The reactionmixture was reacted under hydrogen atmosphere (˜40 psi) for 1 h. Thecatalyst was filtered off over celite. The filtrate was evaporated togive 4-(aminocarbonylmethoxy)analine as a white solid.

4-(Aminocarbonylmethoxy)analine (5 g) and2,6-dichloro-5-fluoropyrimidine (6 g) were dissolved in methanol (10 mL)and water (1 mL). The reaction solution was stirred at rt overnight.Then methanol was removed under reduced pressure. The remaining aq.solution was acidified with 1 N HCl aq. (80 mL). The white precipitatewas collected by filtration, washed with water and dried to giveN4-(4-aminocarbonylmethoxy)phenyl-2-chloro-5-fluoro-4-pyrimidineamine asa solid.

N4-(4-Aminocarbonylmethoxy)phenyl-2-chloro-5-fluoro-4-pyrimidineamine (2g) was dissolved in THF (20 mL). To this solution was addedtrifluoroacetic anhydride (1.9 mL) and pyridine (1.65 mL). The reactionsolution was stirred at rt overnight. Then it was diluted with ethylacetate (100 mL). The organic layer was washed with K₂CO₃ aq. (2×100mL), 1 N HCl aq. (100 mL) and water (100 mL). The ethyl acetate layerwas separated, dried and evaporated to give2-chloro-N4-(4-cyanomethoxy)phenyl-5-fluoro-4-pyrimidineamine as a whitesolid.

2-Chloro-N4-(4-cyanomethoxy)phenyl-5-fluoro-4-pyrimidineamine (100 mg)and sulfanilamide (100 mg) were dissolved in isopropanol (1 mL). Thesolution was heated at 100° C. overnight, then diluted with methanol (5mL) and sonicated. The precipitation was filtered off, washed withmethanol and dried to giveN2-(4-aminosulfonyl)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamineas a beige solid. ¹H NMR (DMSO-d₆): δ 5.16 (s, 2H), 7.07 (d, J=9.0 Hz,2H), 7.16 (br, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 7.75(d, J=8.7 Hz, 2H), 8.17 (d, J=4.2 Hz, 1H), 9.71 (br, 1H), 9.85 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.19; LCMS: purity: 95.05%; MS (m/e):415.01 (MH⁺).

The following compounds were made in a similar fashion to the example27.

I-17:N2-(3-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.16 (s, 2H), 7.06 (d, J=9.3 Hz, 2H), 7.31 (br, 2H),7.42 (m, 2H), 7.68 (d, J=9.0 Hz, 2H), 7.87 (m, 1H), 7.94 (s, 1H), 8.19(d, J=4.2 Hz, 1H), 9.90 (br, 1H), 9.97 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −200.94; LCMS: purity: 93.17%; MS (m/e): 415.54 (MH⁺).

I-91:N4-(3-Aminocarbonylmethoxy)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.43 (s, 2H), 6.72 (dd, J=2.1, 7.5 Hz, 1H), 7.16(br, 2H), 7.26 (t, J=8.1 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 7.44 (m, 2H),7.54 (s, 1H), 7.65 (d, J=9.0 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 8.22 (d,J=4.2 Hz, 1H), 9.82 (br, 1H), 9.91 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ −200.39; LCMS: purity: 91.64%; MS (m/e): 433.00 (MH⁺).

I-88:N4-(3-Aminocarbonylmethoxy)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.41 (s, 2H), 6.66 (dd, J=2.4, 8.4 Hz, 1H), 7.23 (t,J=8.1 Hz, 1H), 7.26 (br, 2H), 7.35-7.54 (m, 6H), 7.94 (d, J=8.1 Hz, 1H),8.09 (s, 1H), 8.16 (d, J=4.2 Hz, 1H), 9.62 (br, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.09; LCMS: purity: 94.82%; MS (m/e): 433.46 (MH⁺).

I-3:N2-(4-Aminosulfonyl)phenyl-N4-(3-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.14 (s, 2H), 6.81 (dd, J=2.7, 8.4 Hz, 1H), 7.13(br, 2H), 7.32 (t, J=8.1 Hz, 1H), 7.49 (t, J=2.1 Hz, 1H), 7.54 (d, J=8.1Hz, 1H), 7.63 (d, J=8.7 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 8.18 (d, J=3.6Hz, 1H), 9.55 (br, 1H), 9.62 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.17; LCMS: purity: 93.10%; MS (m/e): 415.56 (MH⁺).

I-4:N2-(3-Aminosulfonyl)phenyl-N4-(3-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.14 (s, 2H), 6.81 (dd, J=2.4, 8.4 Hz, 1H), 7.29(br, 2H), 7.32 (t, J=8.1 Hz, 1H), 7.40 (m, 2H), 7.52 (m, 2H), 7.92 (m,1H), 8.01 (s, 1H), 8.20 (d, J=4.2 Hz, 1H), 9.78 (br, 2H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −200.81; LCMS: purity: 88.73%; MS (m/e): 415.58 (MH⁺).

III-3:N2-(4-Aminosulfonyl)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.01 (s, 2H), 7.15 (br, 2H), 7.32 (d, J=9.0 Hz, 2H),7.65 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H),8.19 (d, J=3.6 Hz, 1H), 9.70 (br, 1H), 9.78 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −200.85; LCMS: purity: 89.03%; MS (m/e): 399.54 (MH⁺).

III-4:N2-(3-Aminosulfonyl)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.00 (s, 2H), 7.29 (br, 2H), 7.30 (d, J=8.4 Hz, 2H),7.39 (m, 2H), 7.78 (d, J=8.1 Hz, 2H), 7.89 (m, 1H), 8.02 (s, 1H), 8.18(d, J=3.9 Hz, 1H), 9.80 (br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.02;LCMS: purity: 98.20%; MS (m/e): 399.53 (MH⁺).

I-18:N4-(4-Cyanomethoxy)phenyl-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine

LCMS: purity: 99.80%; MS (m/e): 498.06 (MH⁺).

I-19:N4-(4-Cyanomethoxy)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.12 (s, 3H), 2.34 (t, 4H), 2.87 (t, 4H), 5.15 (s,2H), 7.05 (d, J=9.0 Hz, 2H), 7.18 (d, J=8.1 Hz, 1H), 7.45 (t, J=8.1 Hz,1H), 7.74 (d, J=8.7 Hz, 2H), 7.98 (s, 1H), 8.11 (d, J=7.8 Hz, 1H), 8.11(d, J=3.6 Hz, 1H), 9.38 (br, 1H), 9.53 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.15; LCMS: purity: 93.41%; MS (m/e): 498.39 (MH⁺).

I-89:N4-(3-Aminocarbonylmethoxy)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.12 (s, 3H), 2.34 (t, 4H), 2.88 (t, 4H), 4.42 (s,2H), 6.66 (dd, J=2.7, 8.4 Hz, 1H), 7.18-7.25 (m, 2H), 7.41-7.56 (m, 5H),8.10 (m, 2H), 8.15 (d, J=3.9 Hz, 1H), 9.44 (br, 1H), 9.51 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.35; LCMS: purity: 86.95%; MS (m/e):516.11 (MH⁺).

I-5:N4-(3-Cyanomethoxy)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.12 (s, 3H), 2.34 (t, 4H), 2.87 (t, 4H), 5.14 (s,2H), 6.78 (dd, J=2.4, 8.1 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 7.31 (t,J=8.1 Hz, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.54 (m, 2H), 8.00 (s, 1H), 8.10(d, J=8.4 Hz, 1H), 8.16 (d, J=3.6 Hz, 1H), 9.48 (br, 1H), 9.55 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.35; LCMS: purity: 91.89%; MS (m/e):498.06 (MH⁺).

III-5:N4-(4-Cyanomethyl)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.12 (s, 3H), 2.34 (t, 4H), 2.87 (t, 4H), 3.99 (s,2H), 7.19 (d, J=7.5 Hz, 1H), 7.30 (d, J=8.7 Hz, 2H), 7.46 (t, J=8.1 Hz,1H), 7.81 (d, J=8.4 Hz, 2H), 8.00 (s, 1H), 8.10 (dd, J=1.5, 8.1 Hz, 1H),8.14 (d, J=3.6 Hz, 1H), 9.48 (br, 1H), 9.56 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.59; LCMS: purity: 93.12%; MS (m/e): 482.06 (MH⁺).

RI-6:N4-(3-Cyanomethoxy)phenyl-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine

LCMS: purity: 99.63%; MS (m/e): 498.05 (MH⁺).

III-6:N4-(4-Cyanomethyl)phenyl-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine

LCMS: purity: 96.81%; MS (m/e): 482.03 (MH⁺).

I-115:N4-(4-Aminocarbonylmethoxy)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.43 (s, 2H), 6.95 (d, J=8.7 Hz, 2H), 7.17 (br, 2H),7.36 (br, 1H), 7.55 (br, 1H), 7.58 (d, J=9.3 Hz, 2H), 7.62 (d, J=8.4 Hz,2H), 7.74 (d, J=8.7 Hz, 2H), 8.16 (d, J=3.9 Hz, 1H), 9.70 (br, 1H), 9.86(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.26; LCMS: purity: 95.49%;MS (m/e): 433.36 (MH⁺).

I-111:N4-(4-Aminocarbonylmethoxy)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.42 (s, 2H), 6.93 (d, J=8.7 Hz, 2H), 7.31 (br, 2H),7.41 (m, 3H), 7.52 (br, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.87 (m, 1H), 7.94(s, 1H), 8.17 (d, J=4.2 Hz, 1H), 9.84 (br, 1H), 9.94 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ −201.04; LCMS: purity: 96.23%; MS (m/e): 433.39(MH⁺).

I-112:N4-(4-Aminocarbonylmethoxy)phenyl-5-fluoro-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.12 (s, 3H), 2.34 (t, 4H), 2.86 (t, 4H), 4.41 (s,2H), 6.92 (d, J=9.0 Hz, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.38 (br, 1H), 7.43(t, J=8.1 Hz, 1H), 7.51 (br, 1H), 7.65 (d, J=9.0 Hz, 2H), 7.97 (s, 1H),8.08 (d, J=3.6 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 9.30 (br, 1H), 9.50 (br,1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.33; LCMS: purity: 77.73%; MS(m/e): 516.44 (MH⁺).

I-65: RacemicN2-(3-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.69 (d, J=6.6 Hz, 3H), 5.41 (q, J=6.6 Hz, 1H), 7.06(d, J=9.0 Hz, 2H), 7.25 (br, 2H), 7.31-7.41 (m, 2H), 7.77 (d, J=8.7 Hz,2H), 7.94 (d, J=8.1 Hz, 1H), 8.09 (m, 2H), 9.35 (br, 1H), 9.49 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.36; LCMS: purity: 91.76%; MS (m/e):429.05 (MH⁺).

I-66: RacemicN2-(4-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.70 (d, J=6.6 Hz, 3H), 5.43 (q, J=6.6 Hz, 1H), 7.09(d, J=9.0 Hz, 2H), 7.13 (br, 2H), 7.63 (d, J=8.7 Hz, 2H), 7.71 (d, J=9.0Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 8.16 (d, J=3.9 Hz, 1H), 9.61 (br, 1H),9.76 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.42; LCMS: purity:96.39%; MS (m/e): 429.39 (MH⁺).

I-116: RacemicN4-[4-(1-Aminocarbonyl)ethoxy]phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.46 (d, J=6.6 Hz, 3H), 4.63 (q, J=6.6 Hz, 1H), 6.92(d, J=9.0 Hz, 2H), 7.19 (br, 3H), 7.57 (d, J=7.8 Hz, 2H), 7.58 (br, 1H),7.63 (d, J=9.0 Hz, 2H), 7.73 (d, J=7.5 Hz, 2H), 8.17 (d, J=4.2 Hz, 1H),9.76 (br, 1H), 9.93 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.11;LCMS: purity: 94.25%; MS (m/e): 447.40 (MH⁺).

I-117: RacemicN4-[4-(1-Aminocarbonyl)ethoxy]phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.44 (d, J=6.6 Hz, 3H), 4.60 (q, J=6.6 Hz, 1H), 6.89(d, J=8.7 Hz, 2H), 7.25 (br, 1H), 7.31 (br, 2H), 7.42 (m, 2H), 7.51 (br,1H), 7.59 (d, J=8.7 Hz, 2H), 7.88 (m, 1H), 7.95 (s, 1H), 8.16 (d, J=4.5Hz, 1H), 9.79 (br, 1H), 9.89 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.17; LCMS: purity: 95.18%; MS (m/e): 447.44 (MH⁺).

I-125:N4-[4-(1-Aminocarbonyl-1-methyl)ethoxy]phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.43 (s, 6H), 6.91 (d, J=8.7 Hz, 2H), 7.16 (br, 2H),7.22 (br, 1H), 7.57 (br, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.62 (d, J=9.9 Hz,2H), 7.74 (d, J=8.4 Hz, 2H), 8.17 (d, J=4.9 Hz, 1H), 9.72 (br, 1H), 9.89(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.14; LCMS: purity: 98.31%;MS (m/e): 461.33 (MH⁺).

I-21:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.16 (s, 2H), 7.06 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.1Hz, 1H), 7.47 (br, 2H), 7.74 (d, J=9.0 Hz, 2H), 8.02 (d, J=8.7 Hz, 1H),8.10 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 9.42 (br, 1H), 9.63 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.94; LCMS: purity: 96.69%; MS (m/e):449.34 (MH⁺).

III-7:N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.51 (s, 3H), 4.00 (s, 2H), 7.21 (d, J=8.1 Hz, 1H),7.29 (br, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.81 (dd,J=2.1, 8.4 Hz, 1H), 8.01 (s, 1H), 8.16 (d, J=4.5 Hz, 1H), 9.75 (br s,1H), 9.82 (br s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.31; LCMS:purity: 96.68%; MS (m/e): 413.66 (MH⁺).

III-8:N2-(3-Aminosulfonyl-4-chloro)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.01 (s, 2H), 7.32 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.7Hz, 1H), 7.49 (br, 2H), 7.79 (d, J=7.8 Hz, 2H), 8.00 (d, J=8.7 Hz, 1H),8.16 (d, J=3.9 Hz, 1H), 8.24 (s, 1H), 9.68 (br s, 1H), 9.79 (br s, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.00; LCMS: purity: 90.19%; MS (m/e):433.00 (MH⁺).

I-75:N2-(4-Aminosulfonyl)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.70 (s, 6H), 7.14 (br, 2H), 7.16 (d, J=9.0 Hz, 2H),7.63 (d, J=8.4 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H),8.18 (d, J=3.9 Hz, 1H), 9.63 (br s, 1H), 9.74 (br s, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.30; LCMS: purity: 94.43%; MS (m/e): 443.64 (MH⁺).

I-274:5-Fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine

4-Nitrophenol (10 g), bromoacetonitrile (6 mL) and K₂CO₃ (15 g) weresuspended in acetone (100 mL). The yellow solution was stirred at rtovernight. The reaction mixture was diluted with water (100 mL) andacetone was removed under reduced pressure. The light-yellow precipitatewas collected by filtration, washed with water and dried to giveO-cyanomethyl-4-nitrophenol.

O-Cyanomethyl-4-nitrophenol (8 g) was dissolved in methanol (50 mL) andto the solution was added hydroxyamine HCl (3.4 g) and triethylamine(9.4 mL). The reaction mixture was refluxed for 4 d and the solvent wasremoved under reduced pressure. The residue was redissolved in THF (50mL). To the solution was added AcCl (23 mL) and triethylamine (50 mL).The reaction mixture was stirred at rt overnight, then added water (30mL) and NaOH (18 g). The reaction solution was refluxed overnight, thendiluted with water (200 mL). The aq. solution was extracted with EtOAc(2×150 mL). After separation, the combined EtOAc layers were dried,evaporated. The residue was purified by flash column chromatography(EtOAc/hexanes=1/2, 1/1, EtOAc) and recrystallized from EtOAc andhexanes to give O-(5-methyl-1,2,4-oxadiazol-3-yl)methyl-4-nitrophenol.

O-(5-Methyl-1,2,4-oxadiazol-3-yl)methyl-4-nitrophenol (1 g) wasdissolved in THF (40 mL) and water (40 mL). Sodium bisulfite (3.8 g),sodium bicarbonate (1.4 g), K₂CO₃ (1.8 g) were added to the solution. Itwas stirred at rt for 30 min, then diluted with water (80 mL). The aq.solution was extracted with EtOAc (2×100 mL). The organic layers werecombined, dried, evaporated to give4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxyaniline.

4-(5-Methyl-1,2,4-oxadiazol-3-yl)methoxyaniline and2,6-dichloro-5-fluoropyrimidine (1 g) were dissolved in methanol (5 mL)and water (1 mL). The reaction solution was stirred at rt for 3d. Thensolution was diluted with water (100 mL) and extracted with ethylacetate (2×100 mL). The organic layers were evaporated to give2-chloro-5-fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-4-pyrimidineamine.

2-Chloro-5-fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-4-pyrimidineamine(80 mg) and [3(4-methylpiperazin-1-yl)sulfonyl]aniline (80 mg) weredissolved in isopropanol (1 mL) and TFA was added (5 drops). Thesolution was heated at 100° C. overnight, then evaporated. The residuewas purified by flash column chromatography (2.0 M NH3/methanol inDCM=1-3%) and recrystallized from ethyl acetate and hexanes to give5-fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-N2-[3-(4-methylpiperazin-1-yl)sulfonyl]phenyl-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 2.12 (s, 3H), 2.35 (t, 4H), 2.61 (s, 3H), 2.87 (t,4H), 5.22 (s, 2H), 7.01 (d, J=9.3 Hz, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.43(t, J=8.1 Hz, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.98 (s, 1H), 8.10 (m, 2H),9.32 (br, 1H), 9.51 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.24;LCMS: purity: 76.41%; MS (m/e): 555.37 (MH⁺).

The following compounds were made in a similar fashion as describedabove.

I-275:N2-(4-Aminosulfonyl)phenyl-5-fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-2,4-pyrimidinediamine

LCMS: purity: 87.52%; MS (m/e): 472.33 (MH⁺).

I-276:N2-(3-Aminosulfonyl)phenyl-5-fluoro-N4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl-2,4-pyrimidinediamine

LCMS: purity: 84.90%; MS (m/e): 472.31 (MH⁺).

I-20:N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

2-Chloro-N4-(4-cyanomethoxy)phenyl-5-fluoro-4-pyrimidineamine (1 g) and2-methyl-5-aminobenzenesulphonamide (1 g) were dissolved in isopropanol(10 mL) and TFA (10 drops). The solution was heated at 100° C.overnight, then diluted with DMF (30 mL). The solution was heated to 50°C. and added water until slightly cloudy. The solution was slowly cooledto rt. The beige precipitation was filtered off, washed with water anddried. The solid was resuspended in methanol and sonicated. The solidwas filtered off, washed with methanol and dried to giveN2-(3-aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-PYrimidinediamine(1.3 g). ¹H NMR (DMSO-d₆): δ 2.50 (s, 3H), 5.16 (s, 2H), 7.05 (d, J=9.0Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.26 (br, 2H), 7.72 (d, J=9.0 Hz, 2H),7.85 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 8.96 (d, J=3.0 Hz, 1H), 9.56 (br,2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.34; LCMS: purity: 95.79%; MS(m/e): 429.51 (MH⁺).

I-76 945941:N2-(3-Aminosulfonyl)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

4-Nitrophenol (5 g), methyl 2-bromoisobutyrate (5.6 mL) and K₂CO₃ (7.5g) were suspended in acetone (60 mL). The yellow solution was refluxedovernight. The reaction mixture was diluted with water (150 mL) andextracted with ethyl acetate (2×100 mL). The organic layers wereevaporated to give methyl 2-(4-nitrophenoxy)isobutyrate.

Methyl 2-(4-nitrophenoxy)isobutyrate was dissolved in methanol (50 mL)and water (50 mL). Sodium hydroxide (5 g) was added. The solution wasstirred at rt for 30 min, then acidified with 1N HCl aq. to pH ˜3. Theaq. Solution was extracted with ethyl acetate (2×100 mL). The organiclayers were evaporated to give 2-(4-nitrophenoxy)isobutyric acid.

2-(4-Nitrophenoxy)isobutyric acid (5 g), isobutyl chloroformate (4.36mL) and triethylamine (8 mL) were stirred in dichloromethane (20 mL) atrt for 1 h. Then 2.0 M ammonia in methanol (20 mL) was added to thesolution. It was stirred at rt for 2 h and evaporated. The mixture waspurified by recrystallization from EtOAc and hexanes to give2-(4-nitrophenoxy)-2-methylpropanamide.

2-(4-Nitrophenoxy)-2-methylpropanamide was dissolved in methanol (50 mL)and to the solution was added 10% Pd—C (500 mg). The reaction mixturewas reacted under hydrogen atmosphere (˜40 psi) for 1 h. The catalystwas filtered off over celite. The filtrate was evaporated to give2-(4-aminophenoxy)-2-methylpropanamide as a white solid.

2-(4-Aminophenoxy)-2-methylpropanamide and2,6-dichloro-5-fluoropyrimidine (2 g) were dissolved in methanol (20 mL)and water (10 mL). The reaction solution was stirred at rt overnight.The solution was diluted with water (100 mL) and sonicated. The whiteprecipitate was collected by filtration, washed with water and dried togiveN4-[4-(1-aminocarbonyl-1-methyl)ethoxylphenyl-2-chloro-5-fluoro-4-pyrimidineamineas a solid.

N4-[4-(1-Aminocarbonyl-1-methyl)ethoxy]phenyl-2-chloro-5-fluoro-4-pyrimidineamine(900 mg) was dissolved in THF (20 mL). To this solution was addedtrifluoroacetic anhydride (0.8 mL) and pyridine (0.7 mL). The reactionsolution was stirred at rt overnight. Then it was diluted with ethylacetate (100 mL). The organic layer was washed with K₂CO₃ aq. (2×100mL), 1 N HCl aq. (100 mL) and water (2×100 mL). The ethyl acetate layerwas separated, dried and evaporated to give2-chloro-N4-[4-(1-cyano-1-methyl)ethoxylphenyl-5-fluoro-4-pyrimidineamineas a white solid.

2-Chloro-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-4-pyrimidineamine(100 mg) and 3-aminobenzenesulfonamide (100 mg) were dissolved inisopropanol (1 mL) and TFA (5 drops). The solution was heated at 100° C.overnight, then diluted with methanol (3 mL) and sonicated. Theprecipitation was filtered off, washed with methanol and dried to giveN2-(3-aminosulfonyl)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamineas a beige solid. ¹H NMR (DMSO-d₆): δ 1.69 (s, 6H), 7.13 (d, J=7.5 Hz,2H), 7.29 (br, 2H), 7.38 (m, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.91 (d, J=6.6Hz, 1H), 8.02 (s, 1H), 8.16 (d, J=2.1 Hz, 1H), 9.70 (br, 1H), 9.75 (br,1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.30; LCMS: purity: 81.69%; MS(m/e): 443.02 (MH⁺).

The following compounds were made in a similar fashion to the previousexample or by methods described herein or know to skilled artisans.

I-126:N4-[4-(1-Aminocarbonyl-1-methyl)ethoxy]phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.41 (s, 6H), 6.88 (d, J=9.3 Hz, 2H), 7.25 (br, 2H),7.34 (m, 3H), 7.53 (br, 1H), 7.69 (d, J=9.0 Hz, 2H), 7.95 (d, J=7.2 Hz,1H), 8.07 (d, J=3.9 Hz, 1H), 8.09 (s, 1H), 9.29 (br, 1H), 9.47 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.34; LCMS: purity: 95.58%; MS (m/e):461.31 (MH⁺).

I-73:N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.69 (s, 6H), 2.49 (s, 3H), 7.12 (d, J=9.0 Hz, 2H),7.18 (d, J=8.4 Hz, 1H), 7.24 (br, 2H), 7.83 (d, J=9.0 Hz, 2H), 7.91 (d,J=8.1 Hz, 1H), 8.08 (s, 1H), 8.08 (d, J=2.7 Hz, 1H), 9.39 (br, 1H), 9.42(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.64; LCMS: purity: 97.27%;MS (m/e): 457.14 (MH⁺).

I-67: RacemicN2-(3-Aminosulfonyl-4-methyl)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.70 (d, J=6.6 Hz, 3H), 2.48 (s, 3H), 5.41 (q, J=6.6Hz, 1H), 7.05 (d, J=9.0 Hz, 2H), 7.17 (d, J=8.7 Hz, 1H), 7.22 (br, 2H),7.76 (d, J=9.0 Hz, 2H), 7.89 (dd, J=2.4, 8.4 Hz, 1H), 8.07 (m, 2H), 9.32(br, 1H), 9.39 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.64; LCMS:purity: 95.10%; MS (m/e): 443.46 (MH⁺).

I-22:N2-(4-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.20 (s, 3H), 5.16 (s, 2H), 7.05 (d, J=9.0 Hz, 1H),7.10 (br, 2H), 7.50 (dd, J=2.7, 8.7 Hz, 1H), 7.58 (d, J=2.7 Hz, 1H),7.60 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 8.11 (d, J=3.3 Hz, 1H),9.33 (br, 1H), 9.58 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.06;LCMS: purity: 95.53%; MS (m/e): 429.51 (MH⁺).

I-23:N2-(3-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.17 (s, 3H), 5.17 (s, 2H), 7.07 (d, J=9.0 Hz, 1H),7.30 (br, 2H), 7.40 (d, J=5.4 Hz, 2H), 7.51 (s, 1H), 7.55 (dd, J=2.7,8.7 Hz, 1H), 7.93 (m, 2H), 8.17 (d, J=4.5 Hz, 1H), 9.80 (br, 1H), 9.92(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.02; LCMS: purity: 98.05%;MS (m/e): 429.64 (MH⁺).

I-24:N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.17 (s, 3H), 2.49 (s, 3H), 5.16 (s, 2H), 7.05 (d,J=8.7 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.25 (br, 2H), 7.52 (d, J=2.1 Hz,1H), 7.57 (d, J=8.7 Hz, 1H), 7.87 (dd, J=2.4, 8.4 Hz, 1H), 7.98 (s, 1H),8.08 (d, J=3.9 Hz, 1H), 9.49 (br, 1H), 9.56 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.28; LCMS: purity: 96.81%; MS (m/e): 443.75 (MH⁺).

I-113:N4-(4-Aminocarbonylmethoxy-3-methyl)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.24 (s, 3H), 4.45 (s, 2H), 6.81 (d, J=9.0 Hz, 1H),7.16 (br, 2H), 7.36 (br, 2H), 7.38 (dd, J=2.1, 8.4 Hz, 1H), 7.46 (d,J=2.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 8.15 (d,J=4.2 Hz, 1H), 9.66 (br, 1H), 9.88 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ −201.17; LCMS: purity: 82.30%; MS (m/e): 447.04 (MH⁺).

I-92:N4-(4-Aminocarbonylmethoxy-3-methyl)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.22 (s, 3H), 4.43 (s, 2H), 6.80 (d, J=8.4 Hz, 1H),7.28 (br, 2H), 7.39 (m, 4H), 7.45 (br, 1H), 7.47 (dd, J=2.4 Hz, 1H),7.94 (m, 2H), 8.12 (d, J=4.2 Hz, 1H), 9.62 (br, 1H), 9.78 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.45; LCMS: purity: 92.52%; MS (m/e):447.44 (MH⁺).

I-114:N4-(4-Aminocarbonylmethoxy-3,5-dimethyl)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.24 (s, 6H), 4.14 (s, 2H), 7.17 (br, 2H), 7.34 (s,2H), 7.48 (br, 1H), 7.59 (br, 1H), 7.62 (d, J=9.0 Hz, 2H), 7.76 (d,J=8.7 Hz, 2H), 8.16 (d, J=3.9 Hz, 1H), 9.53 (br, 1H), 9.81 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.12; LCMS: purity: 93.05%; MS (m/e):461.43 (MH⁺).

I-93:N4-(4-Aminocarbonylmethoxy-3,5-dimethyl)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.23 (s, 6H), 4.13 (s, 2H), 7.25 (s, 2H), 7.33-7.40(m, 4H), 7.47 (br, 1H), 7.59 (br, 1H), 7.99 (s, 1H), 8.04 (d, J=7.2 Hz,1H), 8.08 (d, J=3.9 Hz, 1H), 9.19 (br, 1H), 9.48 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −202.22; LCMS: purity: 73.18%; MS (m/e): 461.58 (MH⁺).

I-25:N2-(4-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.26 (s, 6H), 4.91 (s, 2H), 7.17 (br, 2H), 7.38 (s,2H), 7.63 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 8.20 (d, J=4.2 Hz,1H), 9.70 (br, 1H), 9.96 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−200.66; LCMS: purity: 96.84%; MS (m/e): 443.05 (MH⁺).

I-26:N2-(3-Aminosulfonyl)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.26 (s, 6H), 4.90 (s, 2H), 7.25 (s, 2H), 7.32 (d,J=8.4 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.44 (s, 2H), 7.99 (s, 1H), 8.04(d, J=7.8 Hz, 1H), 8.09 (d, J=3.6 Hz, 1H), 9.25 (br, 1H), 9.50 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.11; LCMS: purity: 93.34%; MS (m/e):443.04 (MH⁺).

I-27:N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.25 (s, 6H), 2.49 (s, 3H), 4.90 (s, 2H), 7.16 (d,J=8.1 Hz, 1H), 7.22 (s, 2H), 7.43 (s, 2H), 7.94 (dd, J=2.1, 8.1 Hz, 1H),8.01 (d, J=2.4 Hz, 1H), 8.06 (d, J=3.6 Hz, 1H), 9.21 (br, 1H), 9.38 (br,1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −217.5; LCMS: purity: 96.48%; MS(m/e): 457.39 (MH⁺).

I-28:N2-(4-Aminosulfonyl-3-methoxyphenyl)-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.67 (s, 3H), 5.14 (s, 2H), 6.80 (s, 2H), 7.04 (d,J=9.0 Hz, 2H), 7.37 (m, 1H), 7.51 (m, 2H), 7.70 (d, J=9.3 Hz, 2H), 8.12(d, 1H), 9.40 (br, 1H), 9.52 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.82; LCMS: purity: 89.30%; MS (m/e): 445.37 (MH⁺).

III-9:N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.70 (s, 3H), 4.00 (s, 2H), 6.82 (s, 2H), 7.30 (d,J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz, 1H), 7.52 (m, 2H), 7.78 (d, J=8.4 Hz,2H), 8.17 (d, J=3.0 Hz, 1H), 9.51 (br, 1H), 9.56 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.21; LCMS: purity: 89.37%; MS (m/e): 429.14 (MH⁺).

I-70: RacemicN2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.69 (s, 3H), 5.41 (q, J=6.6 Hz, 1H), 6.80 (s, 2H),7.06 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.7 Hz, 1H), 7.50 (m, 2H), 7.72 (d,J=9.0 Hz, 2H), 8.13 (d, J=3.3 Hz, 1H), 9.41 (br, 1H), 9.53 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.75; LCMS: purity: 93.14%; MS (m/e):459.17 (MH⁺).

I-60: RacemicN2-(4-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.72 (d, J=6.6 Hz, 3H), 2.20 (s, 3H), 5.37 (q, J=6.6Hz, 1H), 7.11 (d, J=8.7 Hz, 1H), 7.13 (br, 2H), 7.48 (dd, J=2.7, 8.4 Hz,1H), 7.58 (d, J=2.7 Hz, 1H), 7.63 (d, J=9.0 Hz, 2H), 7.74 (d, J=8.7 Hz,2H), 8.18 (d, J=4.2 Hz, 1H), 9.70 (br, 1H), 9.90 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −200.99; LCMS: purity: 97.08%; MS (m/e): 443.15 (MH⁺).

I-61: RacemicN2-(3-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.72 (d, J=6.6 Hz, 3H), 2.18 (s, 3H), 5.36 (q, J=6.6Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.29 (br, 2H), 7.40 (d, J=5.1 Hz, 2H),7.53 (s, 1H), 7.56 (dd, J=2.1, 9.0 Hz, 1H), 7.94 (m, 2H), 8.17 (d, J=3.9Hz, 1H), 9.75 (br, 1H), 9.89 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.06; LCMS: purity: 95.36%; MS (m/e): 443.64 (MH⁺).

I-62: RacemicN2-(3-Aminosulfonyl-4-methyl)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.72 (d, J=6.6 Hz, 3H), 2.16 (s, 3H), 2.50 (s, 3H),5.36 (q, J=6.6 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H),7.29 (br, 2H), 7.50 (s, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.82 (dd, J=2.1,8.1 Hz, 1H), 7.90 (d, 1H), 8.16 (d, J=4.5 Hz, 1H), 9.89 (br, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.19; LCMS: purity: 93.72%; MS (m/e):457.18 (MH⁺).

I-94:N4-(4-Aminocarbonylmethoxy)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.49 (s, 3H), 4.40 (s, 2H), 6.91 (d, J=9.0 Hz, 2H),7.15 (d, J=8.7 Hz, 1H), 7.22 (s, 2H), 7.38 (br, 1H), 7.51 (br, 1H), 7.67(d, J=9.0 Hz, 2H), 7.87 (d, J=6.6 Hz, 1H), 8.03 (d, J=3.9 Hz, 1H), 8.09(s, 1H), 9.23 (br, 1H), 9.35 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−203.07; LCMS: purity: 62.07%; MS (m/e): 447.05 (MH⁺).

I-90:N4-(3-Aminocarbonylmethoxy)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.49 (s, 3H), 4.42 (s, 2H), 6.64 (dd, J=2.7, 8.4 Hz,1H), 7.22 (m, 4H), 7.43 (m, 2H), 7.49 (s, 1H), 7.58 (s, 1H), 7.91 (dd,J=1.8, 8.7 Hz, 1H), 8.09 (d, J=3.0 Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 9.34(br, 1H), 9.36 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.17; LCMS:purity: 83.29%; MS (m/e): 447.13 (MH⁺).

I-118:N4-[4-(1-Aminocarbonyl)ethoxy]phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.44 (d, J=6.6 Hz, 3H), 2.53 (s, 3H), 4.60 (q, J=6.6Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.1 Hz, 1H), 7.24 (br, 1H),7.30 (s, 2H), 7.51 (br, 1H), 7.57 (d, J=9.0 Hz, 2H), 7.76 (d, J=8.1 Hz,1H), 7.92 (s, 1H), 8.15 (d, J=4.8 Hz, 1H), 9.95 (br, 2H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.03; LCMS: purity: 89.00%; MS (m/e): 461.09 (MH⁺).

I-127:N4-[4-(1-Aminocarbonyl-1-methyl)ethoxy]phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.41 (s, 6H), 2.49 (s, 3H), 6.88 (d, J=8.7 Hz, 2H),7.14 (d, J=8.7 Hz, 1H), 7.22 (s, 2H), 7.24 (s, 1H), 7.52 (s, 1H), 7.69(d, J=9.0 Hz, 2H), 7.88 (dd, J=2.4, 8.1 Hz, 1H), 8.04 (d, J=3.6 Hz, 1H),8.09 (d, J=1.8 Hz, 1H), 9.25 (br, 1H), 9.35 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.91; LCMS: purity: 92.68%; MS (m/e): 475.18 (MH⁺).

I-95:N4-(4-Aminocarbonylmethoxy-3-methyl)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.22 (s, 3H), 2.49 (s, 3H), 4.42 (s, 2H), 6.78 (d,J=8.7 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.20 (s, 2H), 7.35 (s, 1H), 7.39(s, 1H), 7.48 (m, 2H), 7.90 (dd, J=2.4, 8.4 Hz, 1H), 8.01 (d, J=3.6 Hz,1H), 8.06 (d, J=2.4 Hz, 1H), 9.14 (br, 1H), 9.32 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −203.12; LCMS: purity: 93.67%; MS (m/e): 461.16 (MH⁺).

I-119: RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3-methyl]phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.47 (d, J=6.6 Hz, 3H), 2.22 (s, 3H), 4.64 (q, J=6.6Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 7.18 (s, 1H), 7.27 (br, 2H), 7.32 (dd,J=2.4, 8.4 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.66 (s, 4H),8.29 (d, J=5.1 Hz, 1H), 10.32 (br, 1H), 10.63 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −199.40; LCMS: purity: 88.84%; MS (m/e): 461.14 (MH⁺).

I-120: RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3-methyl]phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.45 (d, J=6.6 Hz, 3H), 2.19 (s, 3H), 4.58 (q, J=6.6Hz, 1H), 6.76 (d, J=8.7 Hz, 1H), 7.26 (s, 1H), 7.31 (s, 2H), 7.41 (m,5H), 7.86 (s, 1H), 7.93 (d, J=7.5 Hz, 1H), 8.17 (d, J=4.5 Hz, 1H), 9.87(br, 1H), 10.03 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −200.79; LCMS:purity: 87.27%; MS (m/e): 461.08 (MH⁺).

I-96:N4-(4-Aminocarbonylmethoxy-3,5-dimethyl)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.21 (s, 6H), 2.48 (s, 3H), 4.12 (s, 2H), 7.14 (d,J=8.4 Hz, 1H), 7.23 (s, 2H), 7.38 (s, 2H), 7.46 (br, 1H), 7.60 (br, 1H),7.91 (dd, J=8.4 Hz, 1H), 7.99 (d, 1H), 8.03 (d, J=3.6 Hz, 1H), 9.15 (br,1H), 9.33 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.71; LCMS: purity:83.51%; MS (m/e): 475.19 (MH⁺).

I-121: RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3-methyl]phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.45 (d, J=6.6 Hz, 3H), 2.18 (s, 3H), 2.52 (s, 3H),4.58 (q, J=6.6 Hz, 1H), 6.76 (d, J=9.6 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H),7.24 (s, 1H), 7.31 (s, 2H), 7.40 (br, 3H), 7.80 (d, J=8.4 Hz, 1H), 7.86(s, 1H), 8.16 (d, J=4.8 Hz, 1H), 10.02 (br, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −200.86; LCMS: purity: 87.82%; MS (m/e): 475.06 (MH⁺).

I-122: RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3,5-dimethyl]phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.33 (d, J=6.6 Hz, 3H), 2.24 (s, 6H), 4.29 (q, J=6.6Hz, 1H), 7.15 (br, 2H), 7.28 (br, 1H), 7.34 (s, 2H), 7.55 (br, 1H), 7.60(d, J=9.0 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 8.13 (d, J=3.9 Hz, 1H), 9.39(br, 1H), 9.70 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.52; LCMS:purity: 89.76%; MS (m/e): 475.09 (MH⁺).

I-123: RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3,5-dimethyl]phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.32 (d, J=6.6 Hz, 3H), 2.22 (s, 6H), 4.27 (q, J=6.6Hz, 1H), 7.25 (s, 2H), 7.28 (br, 1H), 7.33 (m, 2H), 7.40 (s, 2H), 7.53(br, 1H), 7.98 (s, 1H), 8.05 (m, 1H), 8.07 (d, J=3.6 Hz, 1H), 9.17 (br,1H), 9.48 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.22; LCMS: purity:90.76%; MS (m/e): 475.12 (MH⁺).

I-124: RacemicN4-[4-(1-Aminocarbonyl)ethoxy-3,5-dimethyl]phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.32 (d, J=6.6 Hz, 3H), 2.22 (s, 6H), 2.49 (s, 3H),4.27 (q, J=6.6 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.23 (s, 2H), 7.28 (s,1H), 7.39 (s, 2H), 7.54 (s, 1H), 7.94 (dd, J=2.1, 8.4 Hz, 1H), 8.01 (d,J=2.4 Hz, 1H), 8.04 (d, J=3.6 Hz, 1H), 9.13 (br, 1H), 9.36 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −202.79; LCMS: purity: 96.27%; MS (m/e):489.17 (MH⁺).

I-63: RacemicN2-(4-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy-3,5-dimethyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.71 (d, J=6.6 Hz, 3H), 2.27 (s, 6H), 5.01 (q, J=6.6Hz, 1H), 7.16 (br, 2H), 7.39 (s, 2H), 7.64 (d, J=9.0 Hz, 2H), 7.74 (d,J=9.3 Hz, 2H), 8.20 (d, J=3.9 Hz, 1H), 9.72 (br, 1H), 9.98 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −200.54; LCMS: purity: 97.32%; MS (m/e):457.15 (MH⁺).

I-71: RacemicN2-(3-Aminosulfonyl)phenyl-N4-[4-(1-cyano)ethoxy-3,5-dimethyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.71 (d, J=6.6 Hz, 3H), 2.25 (s, 6H), 5.01 (q, J=6.6Hz, 1H), 7.31 (s, 2H), 7.40 (s, 4H), 7.87 (s, 1H), 7.99 (m, 1H), 8.20(d, J=4.2 Hz, 1H), 9.78 (br, 1H), 9.98 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −200.67; LCMS: purity: 99.05%; MS (m/e): 457.59 (MH⁺).

I-72: RacemicN2-(3-Aminosulfonyl-4-methyl)phenyl-N4-[4-(1-cyano)ethoxy-3,5-dimethyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.71 (d, J=6.6 Hz, 3H), 2.25 (s, 6H), 2.50 (s, 3H),5.01 (q, J=6.6 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.30 (s, 2H), 7.40 (s,2H), 7.89 (m, 2H), 8.16 (d, J=4.5 Hz, 1H), 9.74 (br, 1H), 9.83 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.19; LCMS: purity: 97.45%; MS (m/e):471.60 (MH⁺).

I-7:N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-(3-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.72 (s, 3H), 5.13 (s, 2H), 6.80 (dd, J=9.3 Hz, 1H),6.82 (br, 2H), 7.31 (t, J=8.1 Hz, 1H), 7.39 (d, 1H), 7.51 (m, 4H), 8.18(d, J=3.6 Hz, 1H), 9.51 (br, 1H), 9.55 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.04; LCMS: purity: 91.71%; MS (m/e): 445.00 (MH⁺).

I-77:N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.70 (s, 6H), 3.72 (s, 3H), 6.80 (s, 2H), 7.13 (d,J=8.7 Hz, 2H), 7.43 (m, 1H), 7.49 (m, 2H), 7.80 (d, J=8.7 Hz, 2H), 8.15(d, J=3.6 Hz, 1H), 9.48 (br, 1H), 9.56 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.44; LCMS: purity: 84.88%; MS (m/e): 473.10 (MH⁺).

I-29:N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.17 (s, 3H), 3.66 (s, 3H), 5.16 (s, 2H), 6.80 (br,2H), 7.04 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 7.51 (m, 4H), 8.11 (d, J=3.6Hz, 1H), 9.33 (br, 1H), 9.52 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.86; LCMS: purity: 70.82%; MS (m/e): 459.02 (MH⁺).

I-32:N2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.24 (s, 6H), 3.68 (s, 3H), 4.89 (s, 2H), 6.81 (s,2H), 7.36 (dd, J=1.8, 8.4 Hz, 1H), 7.41 (s, 2H), 7.44 (d, J=1.5 Hz, 1H),7.51 (d, J=8.7 Hz, 1H), 8.12 (d, J=3.9 Hz, 1H), 9.30 (br, 1H), 9.53 (br,1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.49; LCMS: purity: 70.55%; MS(m/e): 472.94 (MH⁺).

I-64: RacemicN2-(4-Aminosulfonyl-3-methoxy)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.71 (d, J=6.6 Hz, 3H), 2.18 (s, 3H), 3.67 (s, 3H),5.34 (q, J=6.6 Hz, 1H), 6.80 (br, 2H), 7.08 (d, J=8.4 Hz, 1H), 7.36 (d,J=8.7 Hz, 1H), 7.53 (m, 4H), 8.12 (d, J=2.7 Hz, 1H), 9.34 (br, 1H), 9.53(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.78; LCMS: purity: 77.96%;MS (m/e): 473.14 (MH⁺).

I-33:N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-(4-cyanomethoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.16 (s, 2H), 7.07 (d, J=9.3 Hz, 2H), 7.31 (t, J=9.3Hz, 1H), 7.61 (s, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.88 (m, 2H), 8.20 (d,J=4.8 Hz, 1H), 10.04 (br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −200.77,−158.04; LCMS: purity: 97.97%; MS (m/e): 433.69 (MH⁺).

III-10:N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-(4-cyanomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.00 (s, 2H), 7.28 (t, J=9.3 Hz, 1H), 7.31 (d, J=8.4Hz, 2H), 7.59 (s, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.92 (dd, J=3.6, 8.1 Hz,1H), 7.97 (d, J=3.9 Hz, 1H), 8.17 (d, J=3.9 Hz, 1H), 9.77 (br, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.13, −159.13; LCMS: purity: 99.78%; MS(m/e): 417.57 (MH⁺).

I-68: RacemicN2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-[4-(1-cyano)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 89.22%; MS (m/e): 447.79 (MH⁺).

I-74:N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.69 (s, 6H), 7.14 (d, J=9.0 Hz, 2H), 7.28 (t, J=9.3Hz, 1H), 7.59 (s, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.94 (m, 2H), 8.17 (d,J=3.9 Hz, 1H), 9.81 (br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.14,−159.13; LCMS: purity: 100%; MS (m/e): 461.72 (MH⁺).

I-34:N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-(4-cyanomethoxy-3-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.16 (s, 3H), 5.17 (s, 2H), 7.07 (d, J=8.7 Hz, 1H),7.27 (t, J=9.3 Hz, 1H), 7.46 (d, J=2.1 Hz, 1H), 7.54 (dd, J=2.4, 8.7 Hz,1H), 7.60 (s, 2H), 7.92 (m, 2H), 8.16 (d, J=4.2 Hz, 1H), 9.82 (br, 1H),9.90 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.08, −158.67; LCMS:purity: 99.77%; MS (m/e): 447.69 (MH⁺).

I-35:N2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-(4-cyanomethoxy-3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 96.22%; MS (m/e): 461.84 (MH⁺).

I-69: RacemicN2-(3-Aminosulfonyl-4-fluoro)phenyl-N4-[4-(1-cyano)ethoxy-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.72 (d, J=6.6 Hz, 3H), 2.17 (s, 3H), 5.36 (q, J=6.6Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 7.26 (t, J=9.3 Hz, 1H), 7.49 (s, 1H),7.59 (m, 3H), 7.92 (m, 2H), 8.14 (d, J=4.2 Hz, 1H), 9.73 (br, 1H), 9.82(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.28, −158.94; LCMS: purity:99.33%; MS (m/e): 461.74 (MH⁺).

Example 28

VII-9:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[2-amino-3-methoxypyrid-6-yl]-5-fluoro-2,4-pyrimidinediamine(66)

A mixture ofN4-[2-(tert-butylcarbonyl)amino-3-methoxypyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine(65) (25 mg, 0.07 mmol) and 3-aminosulfonyl-4-methylaniline (15 mg) inmethanol (1 mL) was shaken in a sealed tube at 100° C. for 48 h. Thereaction mixture was then chromatographed (silica gel, CH₂Cl₂ then 2-4%2N NH₃/MeOH in CH₂Cl₂) to obtainN2-(3-aminosulfonyl-4-methylphenyl)-N4-(2-amino-3-methoxypyrid-6-yl)-5-fluoro-2,4-pyrimidinediamine(66). (Note: The N-tert-butylcarbonyl group was cleaved during thisreaction to give free amine function). LCMS: purity: 90%; MS (m/z): 420(MH⁺).

The following compounds were made in a similar fashion to the example28.

VII-7:N2-(3-Aminosulfonylphenyl)-N4-(2-amino-3-methoxypyrid-6-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 92%; MS (m/z): 406 (MH⁺).

VII-8:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(2-amino-3-methoxypyrid-6-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 92%; MS (m/z): 440 (MH⁺).

VII-10:N4-(2-Amino-3-methoxypyrid-6-yl)-N2-[3-(ethoxycarbonylmethylene)aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 93%; MS (m/z): 526 (MH⁺).

VI-96:N2-(3-Butylaminosulfonylphenyl)-N4-(3-cyano-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.63 (s, 1H), 9.60 (s, 1H), 8.20-8.19 (d, J=3.0 Hz,1H), 8.17-8.16 (d, J=3.0 Hz, 1H), 8.02-7.99 (d, J=9.0 Hz, 2H), 7.48-7.38(m, 3H), 7.30-7.27 (d, J=9.0 Hz, 2H), 2.74-2.70 (m, 2H), 2.45 (s, 3H),1.36-1.31 (m, 2H), 1.26-1.18 (m, 2H), 0.81-0.76 (m, 3H); LCMS (m/z):455.02 (M⁺).

VI-97:N2-(3-Butylaminosulfonylphenyl)-N4-(3-chloro-4-fluorophenyl)5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.60 (s, 1H), 9.55 (s, 1H), 8.17-8.16 (d, J=3.0 Hz,1H), 8.03-8.00 (m, 2H), 7.97 (br s, 1H), 7.82-7.76 (m, 1H), 7.48-7.44(m, 1H), 7.42 (s, 1H), 7.39-7.33 (m, 1H), 7.30-7.27 (br d, J=9.0 Hz,1H), 2.76-2.70 (m, 2H), 1.37-1.29 (m, 2H), 1.26-1.18 (m, 2H), 0.81-0.76(m, 3H); LCMS (m/z): 470.33 (M⁺).

VI-98:N2-(3-Aminosulfonylphenyl)-N4-(3-cyano-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.72 (s, 1H), 9.66 (s, 1H), 8.39-8.36 (m, 1H),8.20-8.19 (d, J=3.0 Hz, 1H), 8.08 (br s, 2H), 7.93-7.90 (d, J=9.0 Hz,1H), 7.51-7.34 (m, 3H), 7.27 (s, 2H); LCMS (m/z): 403.18 (M⁺).

VI-99:N2-(3-Aminosulfonylphenyl)-N4-(3-cyano-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.63 (s, 1H), 9.59 (s, 1H), 8.21-8.20 (d, J=3.0 Hz,1H), 8.17-8.16 (d, J=3.0 Hz, 1H), 8.07 (s, 1H), 8.00-7.94 (m, 2H),7.45-7.34 (m, 3H), 7.27 (s, 2H), 2.45 (s, 3H); LCMS (m/z): 399.32 (M⁺).

X-3:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(2-methylindol-5-ylmethylene)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.77 (s, 1H), 9.36 (s, 1H), 8.27 (s, 1H), 7.99 (m,1H), 7.88-7.87 (d, J=3 Hz, 1H), 7.83-7.81 (d, J=6.0 Hz, 1H), 7.35-6.88(m, 4H), 6.70-6.66 (d, J=12 Hz, 2H), 6.03 (s, 1H), 4.66-4.64 (d, J=6 Hz,2H), 2.33 (s, 3H); LCMS (m/z): 427.20 (M⁺).

Example 29

I-30:N4-(4-Cyanomethyleneoxy)phenyl-5-fluoro-N2-(4-methyl-3-propionylaminosulfonyl)phenyl-2,4-pyrimidinediamine(68)

N2-(3-Aminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine(67) (400 mg), propionic anhydride (0.24 mL), N,N-dimethylaminopyridine(DMAP) (60 mg) and triethylamine (0.16 mL) were stirred in THF (15 mL)at room temperature overnight. The solution was diluted with ethylacetate (100 mL) and washed with water (100 mL), and brine (100 mL). Theorganic layer was then evaporated. The residue was recrystallized fromEtOAc and hexanes to giveN4-(4-cyanomethyleneoxy)phenyl-5-fluoro-N2-(4-methyl-3-propionylaminosulfonyl)phenyl-2,4-pyrimidinediamine(68). ¹H NMR (DMSO-d₆): δ 0.88 (t, J=7.5 Hz, 3H), 2.24 (q, J=7.5 Hz,2H), 2.49 (s, 3H), 5.15 (s, 2H), 7.04 (d, J=9.3 Hz, 2H), 7.20 (d, J=8.1Hz, 1H), 7.75 (d, J=9.0 Hz, 2H), 8.00 (dd, J=2.1, 8.1 Hz, 1H), 8.08 (d,J=3.9 Hz, 1H), 8.14 (s, 1H), 9.35 (br, 1H), 9.48 (br, 1H), 12.02 (br,1H); ¹⁹F NMR (DMSO-d₆): δ −202.71; LCMS: purity: 95.67%; MS (m/z):485.09 (MH⁺).

I-31:N4-(4-Cyanomethyleneoxy)phenyl-5-fluoro-N2-(4-methyl-3-propionylaminosulfonyl)phenyl-2,4-pyrimidinediaminesodium salt (69)

N4-(4-Cyanomethoxy)phenyl-5-fluoro-N2-(4-methyl-3-propionylaminosulfonyl)phenyl-2,4-pyrimidinediamine(68) (583.5 mg) was dissolved in methanol (5 mL) and water (1 mL). Tothe solution was added 1 N NaOH aq. (1.2 mL). The solution was thenevaporated and lyophilized to giveN4-(4-cyanomethyleneoxy)phenyl-5-fluoro-N2-(4-methyl-3-propionylaminosulfonyl)phenyl-2,4-pyrimidinediaminesodium salt (69). ¹H NMR (DMSO-d₆): δ 0.85 (t, J=7.5 Hz, 3H), 1.90 (q,J=7.5 Hz, 2H), 2.42 (s, 3H), 5.13 (s, 2H), 6.94 (d, J=8.1 Hz, 1H), 7.04(d, J=9.0 Hz, 2H), 7.70 (d, J=7.5 Hz, 1H), 7.78 (d, J=9.0 Hz, 2H), 7.85(d, J=2.1 Hz, 1H), 8.02 (d, J=3.9 Hz, 1H), 9.17 (br, 1H), 9.22 (br, 1H);¹⁹F NMR (DMSO-d₆): δ −203.90; LCMS: purity: 100%; MS (m/z): 485.39(MH⁺).

The following compounds were made in a similar fashion to the example29.

I-36:N2-(3-Acetylaminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.94 (s, 3H), 2.47 (s, 3H), 5.15 (s, 2H), 7.04 (d,J=9.0 Hz, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.75 (d, J=9.0 Hz, 2H), 8.02 (dd,J=2.4, 8.4 Hz, 1H), 8.08 (d, J=3.6 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 9.34(br, 1H), 9.48 (br, 1H), 12.06 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−202.71; LCMS: purity: 99.34%; MS ((m/z): 471.71 (MH⁺).

I-37:N4-(4-Cyanomethyleneoxy)phenyl-5-fluoro-N2-(3-isobutyrylaminosulfonyl-4-methyl)phenyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.94 (d, J=6.9 Hz, 6H), 2.47 (m, 1H), 2.47 (s, 3H),5.15 (s, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.19 (d, J=8.7 Hz, 1H), 7.75 (d,J=9.3 Hz, 2H), 7.97 (dd, J=2.4, 8.4 Hz, 1H), 8.07 (d, J=3.6 Hz, 1H),8.15 (d, J=2.1 Hz, 1H), 9.34 (br, 1H), 9.47 (br, 1H), 12.02 (br, 1H);¹⁹F NMR (DMSO-d₆): δ −202.77; LCMS: purity: 94.84%; MS (m/z): 499.74(MH⁺).

I-38:N2-(3-Acetylaminosulfonyl-4-methyl)phenyl-N4-(4-cyanomethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediaminesodium salt

¹H NMR (DMSO-d₆): δ 1.63 (s, 3H), 2.42 (s, 3H), 5.13 (s, 2H), 6.95 (d,J=8.4 Hz, 1H), 7.03 (d, J=9.3 Hz, 2H), 7.71 (d, J=8.1 Hz, 1H), 7.78 (d,J=9.3 Hz, 2H), 7.84 (d, J=2.4 Hz, 1H), 8.02 (d, J=3.6 Hz, 1H), 9.18 (br,1H), 9.22 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −203.87; LCMS: purity:91.01%; MS (m/z): 471.18 (MH⁺).

I-39:N4-(4-Cyanomethyleneoxy)phenyl-5-fluoro-N2-(3-isobutyrylaminosulfonyl-4-methyl)phenyl-2,4-pyrimidinediamineSodium Salt

¹H NMR (DMSO-d₆): δ 0.88 (d, J=6.9 Hz, 6H), 2.09 (p, J=6.9 Hz, 1H), 2.42(s, 3H), 5.13 (s, 2H), 6.94 (d, J=7.8 Hz, 1H), 7.04 (d, J=8.7 Hz, 2H),7.68 (d, J=5.7 Hz, 1H), 7.78 (d, J=9.3 Hz, 2H), 7.86 (s, 1H), 8.02 (d,J=3.9 Hz, 1H), 9.17 (br, 1H), 9.22 (br, 1H); ¹⁹F NMR (DMSO-d₆): δ−203.93; LCMS: purity: 91.73%; MS (m/z): 499.38 (MH⁺).

I-48:N4-(4-Cyanomethoxy-3-fluorophenyl)-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.89 (t, J=7.5 Hz, 3H), 2.24 (q, J=7.5 Hz, 2H), 2.48(s, 3H), 5.20 (s, 2H), 7.25 (m, 2H), 7.58 (d, J=9.9 Hz, 1H), 7.94 (dd,J=2.7, 13.8 Hz, 1H), 8.02 (dd, J=2.7, 8.4 Hz, 1H), 8.12 (d, J=3.6 Hz,1H), 8.16 (d, J=2.1 Hz, 1H), 9.50 (br, 1H), 9.58 (br, 1H), 12.03 (br,1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −171.26, −202.29; LCMS: purity:95.69%; MS (m/e): 503.74 (MH⁺).

I-49:N4-(4-Cyanomethoxy-3-fluorophenyl)-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamineSodium Salt

¹H NMR (DMSO-d₆): δ 0.85 (t, J=7.5 Hz, 3H), 1.93 (q, 2H), 2.43 (s, 3H),5.19 (s, 2H), 6.98 (d, J=7.8 Hz, 1H), 7.27 (t, J=9.3 Hz, 1H), 7.66 (d,J=9.9 Hz, 1H), 7.75 (d, 1H), 7.88 (m, 1H), 7.95 (d, 1H), 8.07 (d, J=3.6Hz, 1H), 9.32 (br, 1H), 9.38 (br, 1H); LCMS: purity: 84.54%; MS (m/e):503.45 (MH⁺).

VI-12:N2-[3-(N-Acetypaminosulfonyl-4-chlorophenyl]-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 89%, MS (m/e): 501 (MH⁺).

I-264:5-Fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-N2-[(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 11.96 (s, 1H), 9.56 (s, 1H), 9.33 (s, 1H),8.17 (s, 1H), 8.07 (m, 2H), 7.69 (d, 2H, J=8.7 Hz), 7.37 (m, 2H), 7.01(d, 2H, J=9.0 Hz), 5.46 (s, 2H), 2.36 (s, 3H), 2.22 (q, 2H, J=7.5 Hz),0.88 (t, 3H, J=7.5 Hz); LCMS (m/z): 528 (MH⁺).

I-273:5-Fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-N2-[(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediamineSodium Salt

¹H NMR (D₂O, 300 MHz): δ 7.61 (s, 1H), 7.51 (s, 1H), 7.45 (d, 1H, J=7.5Hz), 7.26 (d, 1H, J=7.5 Hz), 7.11 (d, 2H, J=6.9 Hz), 7.00 (t, 1H, J=7.8Hz), 6.67 (d, 2H, J=7.5 Hz), 5.16 (s, 2H), 2.26 (s, 3H), 2.03 (q, 2H,J=7.5 Hz), 0.86 (t, 3H, J=7.8 Hz); LCMS (m/z): 528 (MH⁺).

III-68:5-Fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-N2-[(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 11.95 (s, 1H), 9.55 (s, 1H), 9.37 (s, 1H),8.44 (d, 2H, J=4.8 Hz), 8.17 (s, 1H), 8.09 (d, 1H, J=3.3 Hz), 8.04 (d,1H, J=7.5 Hz), 7.70 (d, 2H, J=8.4 Hz), 7.34 (m, 2H), 7.22 (m, 4H), 3.94(s, 2H), 2.21 (q, 2H, J=7.5 Hz), 0.88 (t, 3H, J=7.2 Hz); LCMS (m/z): 507(MH⁺).

III-69:5-Fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-N2-[(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediaminesodium salt

¹H NMR (D₂O, 300 MHz): δ 8.06 (s, 2H), 7.46 (d, 1H, J=3.6 Hz), 7.33 (m,2H), 7.08 (d, 1H, J=7.8 Hz), 6.79 (br s, 3H), 6.50 (d, 2H, J=8.1 Hz),6.41 (t, 2H, J=7.8 Hz), 3.44 (s, 2H), 2.01 (q, 2H, J=7.5 Hz), 0.84 (t,3H, J=7.2 Hz); LCMS (m/z): 507 (MH⁺).=

I-232:N2-(3-Acetamidosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 12.05 (br s, 1H), 9.60 (s, 1H), 9.36 (s,1H), 8.21 (s, 1H), 8.12 (s, 1H), 8.12 (s, 1H), 7.73 (d, 2H, J=8.7 Hz),7.33 (m, 2H), 7.42 (s, 2H), 7.15 (s, 1H), 7.04 (d, 2H, J=8.7 Hz), 6.38(s, 1H), 5.18 (s, 2H), 2.45 (s, 3H), 1.96 (s, 3H); LCMS (m/z): 513(MH⁺).

I-236:5-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 11.96 (s, 1H), 9.55 (s, 1H), 9.31 (s, 1H),8.17 (s, 1H), 8.06 (m, 2H), 7.68 (d, 2H, J=9.0 Hz), 7.37 (d, 2H, J=5.1Hz), 6.99 (d, 2H, J=9.0 Hz), 6.33 (s, 1H), 5.13 (s, 2H), 2.41 (s, 3H),2.21 (q, 2H, J=7.8 Hz), 0.88 (t, 3H), 2.46 (s, 3H J=7.5 Hz); LCMS (m/z):527 (MH⁺).

I-242:5-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(3-N-propanamido)sulfonylphenyl)]-2,4-pyrimidinediaminesodium salt

¹H NMR (D₂O): δ 7.54 (d, 1H, J=2.1 Hz), 7.42 (br s, 2H), 7.21 (d, 1H,J=7.2 Hz), 6.98 (d, 2H, J=6.9 Hz), 6.83 (t, 1H, J=6.3 Hz), 6.55 (d, 2H,J=6.9 Hz), 5.99 (s, 1H), 4.86 (s, 2H), 2.23 (s, 3H), 2.01 (q, 2H, J=7.8Hz), 0.83 (t, 3H,), 2.46 (s, 3H J=7.5 Hz); LCMS (m/z): 527 (MH⁺).

I-243:N2-(3-Acetamidosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediaminesodium salt

¹H NMR (D₂O): δ 7.59 (s, 1H), 7.47 (s, 2H), 7.22 (d, 1H, J=7.2 Hz), 7.08(d, 2H, J=7.0 Hz), 6.94 (t, 1H, J=6.3 Hz), 6.67 (d, 2H, J=7.8 Hz), 6.05(s, 1H), 4.94 (s, 2H), 2.24 (s, 3H), 1.77 (s, 3H); LCMS (m/z): 513(MH⁺).

I-228:5-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 12.00 (s, 1H), 9.43 (s, 1H), 9.25 (s, 1H), 8.16-8.13(m, 1H), 8.04 (d, J=3.6 Hz, 1H), 8.00-7.95 (m, 1H), 7.68 (d, J=9.0 Hz,2H), 7.17 (d, JH=9.0 Hz, 1H), 6.97 (d, J=9.0 Hz, 2H), 6.31 (s, 1H), 5.12(s, 2H), 2.49 (s, 3H), 2.23 (q, J=7.2 Hz, 2H), 0.88 (t, J=7.2 Hz, 2H);LCMS: purity: 97%; MS (m/e): 542 (MH⁺).

I-229:5-Fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N2-(4-methyl-3-(2-methylpropionyl)aminosulfonylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 12.00 (s, 1H), 9.43 (s, 1H), 9.25 (s, 1H), 8.18-7.15(m, 1H), 8.04 (d, J=3.6 Hz, 1H), 7.99-7.09 (m, 1H), 7.68 (d, J=9.0H,2H), 7.17 (d, J=8.7 Hz, 1H), 6.97 (d, J=9.0 Hz, 2H), 6.31 (s, 1H), 5.12(s, 2H), 2.48-2.46 (m, 4H), 2.41 (s, 3H), 0.93 (d, J=6.9 Hz, 6H); LCMS:purity: 94%; MS (m/e): 556 (MH⁺).

Example 30

I-277:N2-(3-aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(71)

2-Chloro-5-fluoro-N4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)methyleneoxyphenyl]-4-pyrimidineamine(70) (100 mg, 0.3 mmol) was added to t-butanol (1 mL), followed by3-aminobenzenesulfonamide (61.5 mg, 0.35 mmol) and a catalytic amount ofacetic acid (10% by mole). The mixture was heated at 100° C. overnightand the solvent was removed under reduced pressure. The residue wasdissolved in ethyl acetate and washed with saturated sodium bicarbonate.The organic layer was separated, dried with sodium sulfate, and thenconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica gel, ethyl acetate: hexanes 3:1) to give20 mg ofN2-(3-aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(71) as a white solid. ¹H NMR (DMSO-d₆): δ 9.47 (s, 1H), 9.30 (s, 1H),8.08 (br s, 2H), 7.94 (br s, 1H), 7.73-7.70 (bd, J=9.0 Hz, 2H),7.39-7.36 (d, J=9.0 Hz, 2H), 7.25 (br s, 2H), 7.04-7.01 (br s, J=9.0 Hz,2H), 5.33 (br s, 2H), 2.55 (s, 3H); LCMS (m/z): 472.13 (MH⁺).

The following compounds were made in a similar fashion to the example30.

I-278:N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.431 (s, 1H), 9.30 (s, 1H), 8.05 (br s, 2H),7.97-7.94 (m, 1H), 7.71-7.68 (d, J=9.0 Hz, 2H), 7.54 (s, 2H), 7.27-7.21(m, 1H), 7.05-7.02 (d, J=9.0 Hz, 2H), 5.34 (s, 2H), 2.53 (s, 3H); LCMS(m/z): 489.91 (MH⁺).

I-279:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)methoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.36 (s, 1H), 9.26 (s, 1H), 8.09 (s, 1H), 8.05-8.04(d, J=3.0 Hz, 1H), 7.89-7.86 (d, J=9.0 Hz, 1H), 7.73-7.70 (d, J=9.0 Hz,2H), 7.22 (s, 2H), 7.18-7.15 (d, J=9.0 Hz, 1H), 7.03-7.00 (d, J=9.0 Hz,2H), 5.33 (s, 2H), 2.53 (s, 3H); LCMS (m/z): 486.16 (MH⁺).

Example 31

I-225:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-methyl-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

To a solution ofN2-chloro-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(54, 0.33 g, 1 mmol) in N,N-dimethylformamide (DMF) (1 mL) were addedCs₂CO₃ and dimethyl sulfate (DMS) (1.5 equivalents, each) and thereaction was stirred at room temperature for 24 h. The reaction wasquenched with water and the solid obtained was collected by filtrationto giveN2-chloro-5-fluoro-N4-methyl-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine(72), which was further reacted with 3-aminosulfonyl-4-methylanilineaccording to the procedure given in Example 18 to giveN2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-methyl-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(73). ¹H NMR (DMSO-d₆): δ 9.46 (s, 1H), 8.46 (s, 1H), 7.90 (d, J=5.4 Hz,1H), 7.65 (d, J=6.6 Hz, 1H), 7.30-7.12 (m, 5H), 7.01 (d, J=8.4 Hz, 2H),6.33 (s, 1H), 5.14 (s, 2H), 3.42 (s, 3H), 3.31 (s, 3H), 2.41 (s, 3H);LCMS: purity: 98%; MS (m/z): 499(MH⁺).

The following compounds were made in a similar fashion to the example31.

I-227:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-methoxycarbonylmethyl-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (CDCl₃): δ 8.29 (d, J=2.1 Hz, 1H), 7.78-7.52 (m, 2H), 7.21-7.15(m, 3H), 7.06 (d, J=8.1 Hz, 1H), 6.87 (d, J=9.0 Hz, 2H), 6.03 (s, 1H),5.46 (bs, 2H), 5.03 (s, 2H), 4.48 (s, 2H), 3.47 (s, 3H), 2.53 (s, 3H),2.36 (s, 3H); LCMS: purity: 90%; MS (m/z): 557(MH⁺).

I-226:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-N4-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.50 (s, 1H), 8.45 (d, J=2.1 Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.64 (dd, J=2.4 and 8.4 Hz, 1H), 7.32 (dd, J=2.7 and 12.3 Hz,1H), 7.29-7.14 (m, 4H), 7.10 (d, J=9.0 Hz, 1H), 6.34 (s, 1H), 5.23 (s,2H), 3.43 (s, 3H), 2.49 (s, 3H), 2.41 (s, 3H); LCMS: purity: 99%; MS(m/z): 517(MH⁺).

Example 32

5-chloromethyl-2,4-dihydro-1,2,4-triazol-3-one (74)

Semicarbazide.HCl (5 g, 89 mmol), 2-chloro-1,1,1-trimethoxyethane (12.07mL, 179 mmol) and methanol (50 mL) were combined and stirred at roomtemperature for 3 days, with the reaction monitored by ¹H NMR.Additional 2-chloro-1,1,1-trimethoxyethane (8.77 mL) was added tocomplete the reaction. Methanol was then removed under vacuum. Theresulting residue was extracted with ethyl acetate (500 mL) and washedwith 1N HCl (2×100 mL). The aqueous phase was back extracted with ethylacetate (5×100 mL). The organic layers were then combined, dried overanhydrous sodium sulfate, and solvent was removed under reduced pressureto give 3.1 g of 5-chloromethyl-2,4-dihydro-1,2,4-triazol-3-one (74) asa white powder. ¹H NMR (DMSO-d₆): δ 11.65 (s, 1H), 11.50 (s, 1H), 4.48(s, 2H); LCMS (m/z): 133.90 (M⁺).

I-200:N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(76)

To a solution of 5-chloromethyl-2,4-dihydro-1,2,4-triazol-3-one (35 mg,0.26 mmol) in 2-butanone, were addedN2-(3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(4-hydroxyphenyl)-2,4-pyrimidinediamine(100 mg, 0.25 mmol) and potassium carbonate (35 mg, 0.25 mmol). Theresulting mixture was microwaved at 140° C. for 5 hours, and thenadditional of 5-chloromethyl-2,4-dihydro-1,2,4-triazol-3-one was addedas needed The reaction solvent was removed under a reduced pressure, andthe residual was purified by column chromatography (silica gel,dichloromethane: methanol 8:2 v/v) to give 25 mg ofN2-(3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methoxyphenyl]-2,4-pyrimidinediamine(76) as a light yellow solid. ¹H NMR (D₂O): δ 7.90-7.89 (d, J=3 Hz, 1H),7.60-7.58 (d, J=6 Hz, 1H), 7.34 (bs, 2H), 7.24-7.18 (m, 2H), 7.05-7.02(d, J=9.0 Hz, 2H), 6.65-6.62 (d, J=9.0 Hz, 2H), 5.11 (br s, 2H); LCMS(m/z): 491.05 (MH⁺).

The following compounds were made in a similar fashion to the methodsdescribed in Example 32, or by methods described herein or known toskilled artisans.

VI-100:N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(4-hydroxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 7.99-7.97 (d, J=5.4 Hz, 1H), 7.80-7.77 (m, 1H),7.74-7.69 (m, 1H), 7.34-7.31 (d, J=6.9 Hz, 2H), 7.27-7.21 (t, 2H),6.81-6.78 (d, J=6.9 Hz, 2H), LCMS: 394.34 (MH⁺).

VI-101:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-hydroxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 7.99-7.97 (d, J=5.4 Hz, 1H), 7.81-7.78 (m, 1H),7.74-7.69 (m, 1H), 7.34-7.31 (d, J=6.9 Hz, 2H), 7.27-7.21 (t, 2H),6.81-6.78 (d, J=6.9 Hz, 2H), LCMS: 376.38 (MH⁺).

VI-102:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-hydroxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 7.96-7.94 (d, J=5.7 Hz, 1H), 7.87-7.86 (d, J=2.4 Hz,1H), 7.62-7.58 (d, J=8.4 Hz, 1H), 7.37-7.29 (m, 4H), 6.80-6.77 (d, J=6.6Hz, 2H), 2.66 (s, 3H), LCMS: 390.39 (MH⁺).

I-201:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (CD₃OD): δ 7.91-7.89 (d, J=4.0 Hz, 1H), 7.61-7.52 (m, 2H),7.41-7.39 (m, 2H), 7.31-7.28 (d, J=9.0 Hz, 2H), 6.63-6.60 (d, J=9.0 Hz,2H), 5.03 (s, 2H); LCMS: 473.58 (M⁺).

I-202:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (CD₃OD): δ 7.95-7.94 (d, J=3.0 Hz, 1H), 7.74 (s, 1H), 7.32-7.2(m, 4H), 6.65-6.0 (m, 2H), 5.05 (s, 2H), 2.67 (s, 3H); LCMS (m/z):487.53 (M⁺).

IX-44:N2-(4-Aminosulfonylphenyl)-N4-[3,5-dimethyl-4-(4-methylpiperazin-1-yl]phenyl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 94.62%; MS (m/e): 486.14 (MH⁺).

I-40:N4-(4-Cyanomethoxy-3,5-dimethylphenyl)-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]-2,4-pyrimidinediamine

LCMS: purity: 92.80%; MS (m/e): 526.65 (MH⁺).

I-41:N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-cyanomethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.25 (s, 2H), 7.12 (br, 2H), 7.27 (d, J=9.0 Hz, 1H),7.64 (d, J=8.7 Hz, 2H), 7.70 (dd, J=2.7, 9.0 Hz, 1H), 7.78 (d, J=8.7 Hz,2H), 7.95 (d, J=2.4 Hz, 1H), 8.16 (d, J=3.6 Hz, 1H), 9.52 (br, 1H), 9.67(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.71; LCMS: purity: 75.54%;MS (m/e): 449.36 (MH⁺).

I-42:N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-cyanomethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.25 (s, 2H), 7.28 (m, 3H), 7.38 (m, 2H), 7.78 (dd,J=2.4, 8.7 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.99(s, 1H), 8.17 (d, J=3.6 Hz, 1H), 9.66 (br, 1H), 9.74 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ −201.64; LCMS: purity: 88.17%; MS (m/e): 449.39(MH⁺).

I-43:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-cyanomethoxypheny)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.49 (s, 3H), 5.25 (s, 2H), 7.24 (m, 4H), 7.79 (dd,J=2.7, 9.0 Hz, 1H), 7.87 (m, 1H), 7.88 (d, J=2.7 Hz, 1H), 8.02 (d, J=2.1Hz, 1H), 8.12 (d, J=3.9 Hz, 1H), 9.54 (br, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.43; LCMS: purity: 91.27%; MS (m/e): 463.40 (MH⁺).

I-97:N4-(4-Aminocarbonylmethoxy-3-chlorophenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.56 (s, 2H), 7.01 (d, J=8.7 Hz, 1H), 7.16 (br, 2H),7.39 (br, 1H), 7.41 (br, 1H), 7.57 (dd, J=2.4, 9.0 Hz, 1H), 7.66 (d,J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.83 (d, J=2.4 Hz, 1H), 8.19 (d,J=3.9 Hz, 1H), 9.76 (br, 1H), 9.92 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ −201.07; LCMS: purity: 82.15%; MS (m/e): 467.36 (MH⁺).

I-98:N4-(4-Aminocarbonylmethoxy-3-chlorophenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.54 (s, 2H), 7.00 (d, J=8.7 Hz, 1H), 7.28 (br, 2H),7.39 (m, 4H), 7.67 (dd, J=2.4, 8.7 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.94(dd, J=2.4, 7.2 Hz, 1H), 7.97 (s, 1H), 8.15 (d, J=3.9 Hz, 1H), 9.64 (br,1H), 9.75 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.59; LCMS: purity:82.05%; MS (m/e): 467.37 (MH⁺).

I-99:N4-(4-Aminocarbonylmethoxy-3-chlorophenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.51 (s, 3H), 4.54 (s, 2H), 6.99 (d, J=9.0 Hz, 1H),7.23 (dd, J=3.3, 8.7 Hz, 1H), 7.28 (br, 2H), 7.36 (br, 1H), 7.45 (br,1H), 7.66 (d, J=9.0 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.82 (dd, J=2.4,8.1 Hz, 1H), 7.96 (s, 1H), 8.15 (d, J=4.2 Hz, 1H), 9.76 (br, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.70; LCMS: purity: 80.53%; MS (m/e):481.38 (MH⁺).

I-100:N4-(4-Aminocarbonylmethoxy-3-fluorophenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.52 (s, 2H), 7.04 (t, J=9.0 Hz, 1H), 7.16 (br, 2H),7.40 (m, 2H), 7.49 (br, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.75 (d, J=2.7 Hz,1H), 7.78 (d, J=9.0 Hz, 2H), 8.18 (d, J=3.6 Hz, 1H), 9.70 (br, 1H), 9.85(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −171.66, −201.16; LCMS: purity:94.57%; MS (m/e): 451.63 (MH⁺).

I-101:N4-(4-Aminocarbonylmethoxy-3-fluorophenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.50 (s, 2H), 7.02 (t, J=9.0 Hz, 1H), 7.29 (br, 2H),7.40 (m, 3H), 7.46 (m, 2H), 7.78 (dd, J=2.4, 13.5 Hz, 1H), 7.94 (m, 1H),8.02 (s, 1H), 8.16 (d, J=4.2 Hz, 1H), 9.69 (br, 1H), 9.79 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −171.60, −201.45; LCMS: purity: 91.91%; MS(m/e): 451.59 (MH⁺).

I-102:N4-(4-Aminocarbonylmethoxy-3-fluorophenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.51 (s, 3H), 4.50 (s, 2H), 7.01 (t, J=9.3 Hz, 1H),7.22 (m, 1H), 7.26 (br, 2H), 7.45 (m, 3H), 7.78 (dd, J=14.1 Hz, 1H),7.84 (dd, J=2.4, 8.4 Hz, 1H), 8.02 (s, 1H), 8.12 (d, J=4.2 Hz, 1H), 9.68(br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −171.61, −201.86; LCMS: purity:83.32%; MS (m/e): 465.67 (MH⁺).

I-44:N2-(4-Aminosulfonylphenyl)-N4-(4-cyanomethoxy-3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.22 (s, 2H), 7.15 (br, 2H), 7.28 (t, J=9.0 Hz, 1H),7.51 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.7 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H),7.91 (dd, J=2.4, 13.5 Hz, 1H), 8.20 (d, J=3.9 Hz, 1H), 9.74 (br, 1H),9.84 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −171.30, −201.07; LCMS:purity: 96.50%; MS (m/e): 433.69 (MH⁺).

I-103:N4-(4-Aminocarbonylmethoxy-3-methoxyphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.73 (s, 3H), 4.41 (s, 2H), 6.91 (d, J=8.4 Hz, 1H),7.16 (br, 2H), 7.28 (m, 2H), 7.37 (br, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.76(d, J=7.8 Hz, 2H), 8.16 (d, 1H), 9.59 (br, 1H), 9.79 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ −201.39; LCMS: purity: 86.59%; MS (m/e): 463.57(MH⁺).

I-104:N4-(4-Aminocarbonylmethoxy-3-methoxyphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.72 (s, 3H), 4.40 (s, 2H), 6.89 (d, J=8.7 Hz, 1H),7.27-7.41 (m, 8H), 7.93 (dd, J=2.4, 5.7 Hz, 1H), 7.99 (s, 1H), 8.13 (d,J=4.2 Hz, 1H), 9.60 (br, 1H), 9.73 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ −201.60; LCMS: purity: 83.79%; MS (m/e): 463.01 (MH⁺).

I-105:N4-(4-Aminocarbonylmethoxy-3-methoxyphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.50 (s, 3H), 3.71 (s, 3H), 4.40 (s, 2H), 6.89 (d,J=8.7 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.26 (br, 2H), 7.28 (d, J=2.4 Hz,1H), 7.33 (m, 2H), 7.40 (br, 1H), 7.83 (dd, J=2.4, 8.1 Hz, 1H), 8.02 (s,1H), 8.09 (d, J=3.9 Hz, 1H), 9.59 (br, 2H); LCMS: purity: 88.10%; MS(m/e): 477.53 (MH⁺).

I-45:N2-(4-Aminosulfonylphenyl)-N4-(4-cyanomethoxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.72 (s, 3H), 5.09 (s, 2H), 7.08 (d, J=8.7 Hz, 1H),7.17 (br, 2H), 7.32 (dd, J=2.4, 8.7 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H),7.63 (d, J=9.0 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 8.20 (d, J=4.2 Hz, 1H),9.80 (br, 1H), 9.96 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −200.85;LCMS: purity: 98.23%; MS (m/e): 445.64 (MH⁺).

I-46:N2-(3-Aminosulfonylphenyl)-N4-(4-cyanomethoxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.73 (s, 3H), 5.08 (s, 2H), 7.06 (d, J=8.7 Hz, 1H),7.28 (br, 2H), 7.37 (m, 4H), 7.93 (m, 1H), 8.00 (s, 1H), 8.15 (d, J=4.2Hz, 1H), 9.62 (br, 1H), 9.72 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.58; LCMS: purity: 97.98%; MS (m/e): 445.10 (MH⁺).

I-47:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanomethoxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.49 (s, 3H), 3.73 (s, 3H), 5.08 (s, 2H), 7.05 (d,J=8.7 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.25 (br, 2H), 7.36 (d, J=2.1 Hz,1H), 7.43 (dd, J=2.4, 8.4 Hz, 1H), 7.87 (dd, J=2.1, 7.8 Hz, 1H), 8.04(d, 1H), 8.09 (d, J=3.9 Hz, 1H), 9.51 (br, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.45; LCMS: purity: 92.72%; MS (m/e): 459.50 (MH⁺).

I-106:N4-(4-Aminocarbonylmethoxy-3-hydroxymethylphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.49 (s, 3H), 4.46 (s, 2H), 4.56 (d, J=5.4 Hz, 2H),5.11 (t, J=5.4 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H),7.20 (br, 2H), 7.40 (br, 1H), 7.49 (br, 1H), 7.58 (d, J=2.7 Hz, 1H),7.67 (dd, J=2.7, 9.0 Hz, 1H), 7.89 (dd, J=2.1, 8.1 Hz, 1H), 8.02 (d,J=3.6 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 9.23 (br, 1H), 9.29 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −202.97; LCMS: purity: 82.44%; MS (m/e):477.03 (MH⁺).

I-50:N2-(3-Aminosulfonylphenyl)-N4-(4-cyanomethoxy-3-hydroxymethylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.51 (d, J=5.4 Hz, 2H), 5.12 (t, J=5.4 Hz, 1H), 5.17(s, 2H), 7.07 (d, J=8.7 Hz, 1H), 7.25 (br, 2H), 7.35 (m, 2H), 7.64 (d,J=2.7 Hz, 1H), 7.79 (dd, J=2.4, 8.7 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H),8.04 (s, 1H), 8.08 (d, J=3.6 Hz, 1H), 9.37 (br, 1H), 9.45 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −202.27; LCMS: purity: 82.62%; MS (m/e):445.10 (MH⁺).

I-51:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanomethoxy-3-hydroxymethylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.48 (s, 3H), 4.51 (d, J=5.7 Hz, 2H), 5.10 (t, J=5.4Hz, 1H), 5.16 (s, 2H), 7.06 (d, J=8.7 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H),7.21 (br, 2H), 7.62 (d, J=2.7 Hz, 1H), 7.78 (dd, J=2.7, 9.0 Hz, 1H),7.91 (dd, J=2.4, 8.4 Hz, 1H), 8.04 (d, J=3.6 Hz, 2H), 9.32 (br, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −202.87; LCMS: purity: 87.82%, MS (m/e):459.12 (MH⁺).

I-52:N2-(4-Aminosulfonylphenyl)-N4-[4-cyanomethoxy-3-(1-cyanomethylpyrazol-3-yl)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.25 (s, 2H), 5.48 (s, 2H), 6.80 (d, J=2.4 Hz, 1H),7.06 (br, 2H), 7.23 (d, J=9.0 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.78 (d,J=9.0 Hz, 2H), 7.90 (m, 2H), 8.06 (d, J=2.7 Hz, 1H), 8.13 (d, J=3.6 Hz,1H), 9.53 (br, 1H), 9.56 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.76; LCMS: purity: 92.05%; MS (m/e): 520.46 (MH⁺).

I-53:N2-(3-Aminosulfonylphenyl)-N4-[4-cyanomethoxy-3-(1-cyanomethylpyrazol-3-yl)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.26 (s, 2H), 5.50 (s, 2H), 6.79 (d, J=1.5 Hz, 1H),7.19-7.35 (m, 5H), 7.92 (m, 4H), 8.02 (d, J=2.4 Hz, 1H), 8.17 (d, J=3.9Hz, 1H), 9.82 (br, 1H), 9.89 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.13; LCMS: purity: 94.31%; MS (m/e): 520.16 (MH⁺).

I-54:N2-(3-Aminosulfonyl-4-methylphenyl]-N4-[4-cyanomethoxy-3-(1-cyanomethylpyrazol-3-yl)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.45 (s, 3H), 5.25 (s, 2H), 5.50 (s, 2H), 6.79 (d,J=2.4 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.23 (m, 3H), 7.86 (dd, J=2.4,8.1 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.97 (m, 2H), 8.02 (d, J=2.7 Hz,1H), 8.09 (d, J=4.2 Hz, 1H), 9.53 (br, 1H), 9.66 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −202.24; LCMS: purity: 95.42%; MS (m/e): 534.28 (MH⁺).

I-107:N4-(4-Aminocarbonylmethoxy-3-hydroxymethylphenyfl-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.47 (s, 2H), 4.56 (d, J=5.4 Hz, 2H), 5.12 (t, J=5.7Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 7.24 (br, 2H), 7.32 (m, 2H), 7.41 (br,1H), 7.49 (br, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.67 (dd, J=3.0, 9.3 Hz,1H), 7.97 (d, J=7.8 Hz, 1H), 8.05 (m, 2H), 9.28 (br, 1H), 9.42 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.45; LCMS: purity: 99.96%; MS (m/e):463.68 (MH⁺).

I-55:N2-(3-Aminosulfonylpyrid-4-yl)-N4-(4-cyanomethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 5.17 (s, 2H), 7.11 (d, J=9.0 Hz, 2H), 7.20 (d, J=7.5Hz, 1H), 7.66 (d, J=8.7 Hz, 2H), 8.53 (d, J=3.3 Hz, 1H), 9.04 (dd,J=1.8, 7.5 Hz, 1H), 9.49 (d, J=1.8 Hz, 1H), 9.96 (br, 1H), 10.33 (br,1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −191.46; LCMS: purity: 90.38%; MS(m/e): 416.91 (MH⁺).

I-143:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.66 (d, J=4.5 Hz, 3H), 4.46 (s, 2H), 6.96 (d, J=9.0Hz, 2H), 7.17 (br, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H),7.74 (d, J=8.7 Hz, 2H), 8.05 (q, J=4.5 Hz, 1H), 8.16 (d, J=4.2 Hz, 1H),9.70 (br, 1H), 9.87 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.19;LCMS: purity: 97.92%; MS (m/e): 447.73 (MH⁺).

I-144:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.66 (d, J=4.8 Hz, 3H), 4.44 (s, 2H), 6.93 (d, J=8.7Hz, 2H), 7.27 (br, 2H), 7.37 (m, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.89 (q,J=3.6 Hz, 1H), 8.00 (br, 2H), 8.11 (d, J=3.9 Hz, 1H), 9.58 (br, 1H),9.68 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.64; LCMS: purity:98.07%; MS (m/e): 447.62 (MH⁺).

I-145:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.52 (s, 3H), 2.65 (d, J=4.8 Hz, 3H), 4.45 (s, 2H),6.93 (d, J=9.0 Hz, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.29 (br, 2H), 7.61 (d,J=9.0 Hz, 2H), 7.78 (dd, J=2.1, 8.1 Hz, 1H), 7.95 (s, 1H), 8.02 (q,J=4.5 Hz, 1H), 8.13 (d, J=4.5 Hz, 1H), 9.80 (br, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.31; LCMS: purity: 94.30%; MS (m/e): 461.73 (MH⁺).

I-128:N2-(4-Aminosulfonylphenyl)-N4-(4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.85 (s, 3H), 3.00 (s, 3H), 4.80 (s, 2H), 6.91 (d,J=8.7 Hz, 2H), 7.17 (br, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz,2H), 7.72 (d, J=8.4 Hz, 2H), 8.16 (d, J=3.9 Hz, 1H), 9.76 (br, 1H), 9.93(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.18; LCMS: purity: 95.72%;MS (m/e): 461.70 (MH⁺).

I-129:N2-(3-Aminosulfonylphenyl)-N4-(4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.85 (s, 3H), 3.00 (s, 3H), 4.78 (s, 2H), 6.88 (d,J=8.4 Hz, 2H), 7.24 (br, 2H), 7.33 (m, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.92(d, J=7.8 Hz, 1H), 8.06 (d, J=2.7 Hz, 1H), 8.09 (s, 1H), 9.26 (br, 1H),9.45 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.67; LCMS: purity:89.45%; MS (m/e): 461.77 (MH⁺).

I-130:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.51 (s, 3H), 2.85 (s, 3H), 3.00 (s, 3H), 4.79 (s,2H), 6.88 (d, J=9.0 Hz, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.28 (br, 2H), 7.56(d, J=9.0 Hz, 2H), 7.77 (dd, J=2.4, 8.4 Hz, 1H), 7.97 (d, J=2.1 Hz, 1H),8.11 (d, J=4.5 Hz, 1H), 9.74 (br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.85; LCMS: purity: 97.67%; MS (m/e): 475.80 (MH⁺).

I-56:N2-(3-Aminosulfonyl-4-methoxyphenyl)-N4-(4-cyanomethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.87 (s, 3H), 5.14 (s, 2H), 7.03 (br, 2H), 7.06 (d,J=9.3 Hz, 2H), 7.10 (d, J=8.7 Hz, 1H), 7.67 (d, J=9.0 Hz, 2H), 7.76 (dd,J=2.4, 9.0 Hz, 1H), 7.83 (s, 1H), 8.13 (d, J=4.2 Hz, 1H), 9.70 (br, 1H),9.89 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.85; LCMS: purity:90.15%; MS (m/e): 445.73 (MH⁺).

I-57:N2-(4-Aminosulfonylphenyl)-N4-(4-cyanomethoxyphenyl-5)-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.16 (s, 3H), 5.18 (s, 2H), 7.12 (d, J=9.0 Hz, 2H),7.24 (br, 2H), 7.52 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.64 (d,J=8.7 Hz, 2H), 7.91 (s, 1H), 9.64 (br, 1H), 10.38 (br, 1H); LCMS:purity: 96.78%; MS (m/e): 411.70 (MH⁺).

I-58:N2-(3-Aminosulfonylphenyl)-N4-(4-cyanomethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.10 (s, 3H), 5.15 (s, 2H), 7.04 (d, J=9.0 Hz, 2H),7.23 (br, 2H), 7.29 (m, 2H), 7.67 (d, J=9.0 Hz, 2H), 7.87 (s, 1H), 7.99(d, J=7.8 Hz, 1H), 8.04 (s, 1H), 8.28 (br, 1H), 9.27 (br, 1H); LCMS:purity: 95.23%; MS (m/e): 411.18 (MH+).

I-59:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanomethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.09 (s, 3H), 2.47 (s, 3H), 5.15 (s, 2H), 7.04 (d,J=9.0 Hz, 2H), 7.12 (d, J=8.4 Hz, 1H), 7.20 (br, 2H), 7.67 (d, J=8.7 Hz,2H), 7.84 (s, 1H), 7.92 (dd, J=2.7, 8.1 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H),8.26 (br, 1H), 9.17 (br, 1H); LCMS: purity: 92.97%; MS (m/e): 425.72(MH⁺).

I-108:N4-(4-Aminocarbonylmethoxyphenyl)-N2-(4-aminosulfonylphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.16 (s, 3H), 4.48 (s, 2H), 7.01 (d, J=8.1 Hz, 2H),7.26 (br, 2H), 7.34 (br, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz,2H), 7.58 (br, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.91 (s, 1H), 9.73 (br, 1H),10.56 (br, 1H); LCMS: purity: 96.73%; MS (m/e): 429.17 (MH⁺).

I-109:N4-(4-Aminocarbonylmethoxyphenyl)-N2-(3-aminosulfonylphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.16 (s, 3H), 4.45 (s, 2H), 6.97 (d, J=9.0 Hz, 2H),7.39 (m, 6H), 7.52 (d, J=7.5 Hz, 2H), 7.64 (s, 1H), 7.78 (d, J=9.3 Hz,1H), 7.88 (s, 1H), 9.70 (br, 1H), 10.49 (br, 1H); LCMS: purity: 93.75%;MS (m/e): 429.22 (MH⁺).

I-110:N4-(4-Aminocarbonylmethoxyphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.54 (s, 3H), 4.45 (s, 2H), 6.96 (d,J=8.7 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.35 (br, 2H), 7.39 (br, 1H),7.41 (d, J=9.0 Hz, 2H), 7.54 (br, 1H), 7.64 (dd, J=2.1, 8.1 Hz, 1H),7.70 (d, J=2.1 Hz, 1H), 7.84 (s, 1H), 9.65 (br, 1H), 10.35 (br, 1H);LCMS: purity: 94.04%; MS (m/e): 443.12 (MH⁺).

I-157:N4-(4-Allylaminocarbonylmethoxyphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.77 (t, J=5.4 Hz, 2H), 4.50 (s, 2H), 5.02-5.13 (m,2H), 5.78 (m, 1H), 6.96 (d, J=9.3 Hz, 2H), 7.11 (br, 2H), 7.60 (d, J=8.4Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 8.09 (d, J=3.6Hz, 1H), 8.27 (t, J=5.7 Hz, 1H), 9.34 (br, 1H), 9.56 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ −202.14; LCMS: purity: 92.65%; MS (m/e): 473.14(MH⁺).

I-158:N4-(4-Allylaminocarbonylmethoxyphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.76 (t, J=5.4 Hz, 2H), 4.49 (s, 2H), 5.02-5.13 (m,2H), 5.80 (m, 1H), 6.94 (d, J=9.3 Hz, 2H), 7.27 (br, 2H), 7.37 (m, 2H),7.65 (d, J=9.0 Hz, 2H), 7.90 (td, J=2.1, 6.6 Hz, 1H), 8.01 (s, 1H), 8.10(d, J=4.2 Hz, 1H), 8.26 (t, J=4.5 Hz, 1H), 9.52 (br, 1H), 9.64 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.86; LCMS: purity: 98.60%; MS (m/e):473.22 (MH⁺).

I-159:N4-(4-Allylaminocarbonylmethoxyphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.51 (s, 3H), 3.76 (t, J=5.4 Hz, 2H), 4.50 (s, 2H),5.00-5.12 (m, 2H), 5.79 (m, 1H), 6.94 (d, J=9.3 Hz, 2H), 7.20 (d, J=9.0Hz, 1H), 7.28 (br, 2H), 7.62 (d, J=9.0 Hz, 2H), 7.79 (dd, J=2.7, 8.4 Hz,1H), 7.97 (s, 1H), 8.11 (d, J=4.2 Hz, 1H), 8.26 (t, J=6.0 Hz, 1H), 9.72(br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.73; LCMS: purity: 92.70%;MS (m/e): 487.80 (MH⁺).

I-131:N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.85 (s, 3H), 3.01 (s, 3H), 4.92 (s, 2H), 6.98 (d,J=9.0 Hz, 1H), 7.11 (br, 2H), 7.54 (dd, J=2.7, 9.3 Hz, 1H), 7.63 (d,J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.78 (s, 1H), 8.12 (d, J=3.3 Hz,1H), 9.40 (br, 1H), 9.62 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−202.11; LCMS: purity: 92.42%; MS (m/e): 495.42 (MH⁺).

I-132:N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.85 (s, 3H), 3.00 (s, 3H), 4.92 (s, 2H), 6.96 (d,J=9.0 Hz, 1H), 7.27 (br, 2H), 7.38 (m, 2H), 7.61 (dd, J=2.4, 9.0 Hz,1H), 7.74 (d, J=2.4 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.98 (s, 1H), 8.13(d, J=4.2 Hz, 1H), 9.56 (br, 1H), 9.69 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.89; LCMS: purity: 96.46%; MS (m/e): 495.04 (MH⁺).

I-133:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.49 (s, 3H), 2.85 (s, 3H), 3.00 (s, 3H), 4.92 (s,2H), 6.95 (d, J=9.0 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.24 (br, 2H), 7.62(dd, J=3.0, 9.3 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.85 (dd, J=2.4, 8.4Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 8.09 (d, J=3.6 Hz, 1H), 9.47 (br, 1H),9.53 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.56; LCMS: purity:93.71%; MS (m/e): 509.06 (MH⁺).

I-210:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.47 (m, 4H), 3.54-3.60 (m, 4H), 4.83 (s, 2H), 6.93(d, J=9.0 Hz, 2H), 7.16 (br, 2H), 7.55 (d, J=9.0 Hz, 2H), 7.63 (d, J=9.0Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 8.16 (d, J=4.2 Hz, 1H), 9.72 (br, 1H),9.90 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.25; LCMS: purity:95.60%; MS (m/e): 503.81 (MH⁺).

I-211:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.46 (m, 4H), 3.56-3.60 (m, 4H), 4.82 (s, 2H), 6.90(d, J=9.0 Hz, 2H), 7.30 (br, 2H), 7.40 (m, 2H), 7.57 (d, J=9.0 Hz, 2H),7.85 (m, 1H), 7.95 (s, 1H), 8.15 (d, J=4.5 Hz, 1H), 9.78 (br, 1H), 9.87(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.26; LCMS: purity: 94.18%;MS (m/e): 503.75 (MH⁺).

I-212:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 3.46 (m, 4H), 3.56-3.61 (m, 4H), 4.82 (s, 2H), 6.89(d, J=9.0 Hz, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.29 (br, 2H), 7.56 (d, J=9.0Hz, 2H), 7.75 (dd, J=2.7, 8.4 Hz, 1H), 7.94 (s, 1H), 8.14 (d, J=4.2 Hz,1H), 9.86 (br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.34; LCMS: purity:91.60%; MS (m/e): 517.75 (MH⁺).

III-119:N2-(4-Aminosulfonylphenyl)-N4-(4-ethylaminocarbonylaminomethylphenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.00 (t, J=7.2 Hz, 3H), 3.03 (q, J=7.2 Hz, 2H), 4.18(s, 2H), 7.16 (br, 2H), 7.22 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.7 Hz, 4H),7.76 (d, J=9.0 Hz, 2H), 8.16 (d, J=3.6 Hz, 1H), 9.63 (br, 1H), 9.76 (br,1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.17; LCMS: purity: 100%; MS(m/e): 460.54 (MH⁺).

III-120:N2-(3-Aminosulfonylphenyl]-N4-(4-ethylaminocarbonylaminomethylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.00 (t, J=7.2 Hz, 3H), 3.03 (q, J=7.2 Hz, 2H), 4.16(s, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.28 (br, 2H), 7.38 (m, 2H), 7.66 (d,J=8.4 Hz, 2H), 7.92 (m, 1H), 8.00 (s, 1H), 8.14 (d, J=4.2 Hz, 1H), 9.66(br, 1H), 9.74 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.25; LCMS:purity: 97.96%; MS (m/e): 460.17 (MH⁺).

III-121:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-ethylaminocarbonylaminomethylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.00 (t, J=7.2 Hz, 3H), 3.03 (p, J=7.2 Hz, 2H), 4.16(d, J=5.7 Hz, 2H), 5.85 (t, J=5.4 Hz, 1H), 6.24 (t, J=6.0 Hz, 1H), 7.16(d, J=6.9 Hz, 1H), 7.18 (d, J=8.1 Hz, 2H), 7.22 (br, 2H), 7.71 (d, J=8.4Hz, 2H), 7.90 (dd, J=2.4, 8.1 Hz, 1H), 8.06 (d, J=3.9 Hz, 1H), 8.10 (d,J=2.1 Hz, 1H), 9.30 (br, 1H), 9.37 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ −202.63; LCMS: purity: 88.98%; MS (m/e): 474.75 (MH⁺).

I-146:N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.67 (d, J=4.8 Hz, 3H), 4.57 (s, 2H), 7.02 (d, J=9.0Hz, 1H), 7.14 (br, 2H), 7.60 (dd, J=2.7, 9.0 Hz, 1H), 7.65 (d, J=9.0 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 7.86 (d, J=2.7 Hz, 1H), 7.91 (d, J=5.1 Hz,1H), 8.16 (d, J=3.9 Hz, 1H), 9.58 (br, 1H), 9.75 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.52; LCMS: purity: 97.14%; MS (m/e): 481.41 (MH⁺).

I-147:N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.67 (d, J=4.5 Hz, 3H), 4.56 (s, 2H), 7.00 (d, J=8.7Hz, 1H), 7.28 (br, 2H), 7.39 (m, 2H), 7.68 (dd, J=2.4, 8.7 Hz, 1H), 7.80(d, J=2.4 Hz, 1H), 7.89 (d, J=4.2 Hz, 1H), 7.94 (d, J=2.1, 7.2 Hz, 1H),7.98 (s, 1H), 8.15 (d, J=3.9 Hz, 1H), 9.62 (br, 1H), 9.73 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.68; LCMS: purity: 97.93%; MS (m/e):481.40 (MH⁺).

I-148:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.51 (s, 3H), 2.67 (d, J=4.8 Hz, 3H), 4.56 (s, 2H),7.00 (d, J=9.3 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 7.28 (br, 2H), 7.65 (dd,J=2.4, 8.7 Hz, 1H), 7.79 (d, J=2.7 Hz, 1H), 7.82 (dd, J=2.4, 8.1 Hz,1H), 7.89 (d, J=4.2 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 8.15 (d, J=4.5 Hz,1H), 9.79 (br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.59; LCMS: purity:93.21%; MS (m/e): 495.44 (MH⁺).

I-213:5-Fluoro-N4-(4-methoxycarbonylmethoxyphenyl)-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine

LCMS: purity: 94.24%; MS (m/e): 518.82 (MH⁺).

I-134:N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.86 (s, 3H), 3.01 (s, 3H), 4.97 (s,2H), 7.03 (d, J=9.3 Hz, 1H), 7.24 (br, 2H), 7.37 (dd, J=2.4, 9.0 Hz,1H), 7.58 (d, J=9.0 Hz, 2H), 7.65 (d, J=3.0 Hz, 1H), 7.69 (d, J=8.7 Hz,2H), 7.93 (s, 1H), 9.66 (br, 1H), 10.53 (br, 1H); LCMS: purity: 93.31%;MS (m/e): 491.44 (MH⁺).

I-135:N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.14 (s, 3H), 2.86 (s, 3H), 3.01 (s, 3H), 4.96 (s,2H), 7.00 (d, J=9.0 Hz, 1H), 7.34 (br, 2H), 7.40-7.49 (m, 3H), 7.59 (d,J=2.7 Hz, 1H), 7.70 (s, 1H), 7.84 (d, J=7.2 Hz, 1H), 7.89 (s, 1H), 9.44(br, 1H), 10.24 (br, 1H); LCMS: purity: 96.97%; MS (m/e): 491.47 (MH⁺).

I-136:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.13 (s, 3H), 2.52 (s, 3H), 2.86 (s, 3H), 3.01 (s,3H), 4.96 (s, 2H), 6.98 (d, J=9.0 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 7.34(br, 2H), 7.42 (dd, J=2.4, 8.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.71 (d,J=8.4 Hz, 1H), 7.75 (s, 1H), 7.84 (s, 1H), 9.40 (br, 1H), 10.13 (br,1H); LCMS: purity: 93.42%; MS (m/e): 505.10 (MH⁺).

I-137:N2-(4-Aminosulfonylphenyl)-N4-(4-dimethylaminocarbonylmethoxy-3-fluorophenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.86 (s, 3H), 3.00 (s, 3H), 4.93 (s,2H), 7.06 (t, J=9.0 Hz, 1H), 7.23 (d, J=16.2 Hz, 1H), 7.26 (br, 2H),7.50 (d, J=12.9 Hz, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H),7.92 (s, 1H), 9.66 (br, 1H), 10.51 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ −172.68; LCMS: purity: 98.26%; MS (m/e): 475.63 (MH⁺).

I-138:N2-(3-Aminosulfonylphenyl)-N4-(4-dimethylaminocarbonylmethoxy-3-fluorophenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.86 (s, 3H), 3.00 (s, 3H), 4.93 (s,2H), 7.04 (t, J=9.3 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 7.36 (br, 2H),7.39-7.49 (m, 3H), 7.69 (s, 1H), 7.83 (d, J=6.9 Hz, 1H), 7.89 (s, 1H),9.57 (br, 1H), 10.36 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −172.80;LCMS: purity: 98.80%; MS (m/e): 475.57 (MH⁺).

I-139:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-dimethylaminocarbonylmethoxy-3-fluorophenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.14 (s, 3H), 2.53 (s, 3H), 2.85 (s, 3H), 3.00 (s,3H), 4.92 (s, 2H), 7.02 (t, J=9.0 Hz, 1H), 7.24 (d, J=8.1 Hz, 2H), 7.34(br, 2H), 7.48 (d, J=12.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.76 (s, 1H),7.84 (s, 1H), 9.44 (br, 1H), 10.17 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ −172.82; LCMS: purity: 96.33%; MS (m/e): 489.12 (MH⁺).

I-149:N2-(4-Aminosulfonylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.68 (d, J=4.5 Hz, 3H), 4.61 (s, 2H),7.08 (d, J=9.0 Hz, 1H), 7.26 (br, 2H), 7.42 (dd, J=2.7, 9.0 Hz, 1H),7.60 (d, J=9.0 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 7.71 (d, J=1.8 Hz, 1H),7.93 (s, 2H), 9.60 (br, 1H), 10.45 (br, 1H); LCMS: purity: 90.13%; MS(m/e): 476.99 (MH⁺).

I-150:N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.68 (d, J=4.8 Hz, 3H), 4.60 (s, 2H),7.04 (d, J=9.0 Hz, 1H), 7.36 (br, 2H), 7.46 (m, 4H), 7.63 (d, J=2.4 Hz,1H), 7.83 (d, J=8.7 Hz, 1H), 7.92 (s, 2H), 9.66 (br, 1H), 10.50 (br,1H); LCMS: purity: 85.98%; MS (m/e): 476.96 (MH⁺).

I-151:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.14 (s, 3H), 2.67 (d, J=4.5 Hz, 3H), 4.60 (s, 2H),7.03 (d, J=9.3 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.36 (br, 2H), 7.45 (d,J=9.3 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.69 (d, J=9.3 Hz, 1H), 7.71 (s,1H), 7.86 (s, 1H), 7.91 (d, J=4.8 Hz, 1H), 9.60 (br, 1H), 10.32 (br,1H); LCMS: purity: 98.01%; MS (m/e): 491.00 (MH⁺).

Example 33

VI-82:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-pyrimidinediamine

3-Phenyl-1-propanol (1 mL) and (diethylamino)sulfur trifluoride (1.2 mL)were dissolved in dichloromethane (10 mL). The reaction solution wasstirred at rt for 3 d. The reaction mixture was passed through a shortsilica gel column and washed with dichloromethane. The collectedsolution was evaporated to give 1-fluoro-3-phenylpropane as light yellowoil. ¹H NMR (DMSO-d₆): δ 1.84-2.02 (m, 2H), 2.65 (t, J=7.5 Hz, 2H), 4.34(t, J=5.7 Hz, 1H), 4.50 (t, J=5.7 Hz, 1H), 7.20 (m, 5H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −79.22.

1-Fluoro-3-phenylpropane was dissolved in acetic anhydride (10 mL) andto the solution was added acetic acid (1 mL) and fuming nitric acid (1mL) at 0° C. The reaction mixture was reacted at rt and to 60° C. for 1h, then diluted with ethyl acetate (100 mL). The organic solution waswashed with water (3×100 mL) and brine (100 mL), and evaporated to give1-fluoro-3-(4-nitrophenyl)propane.

1-Fluoro-3-(4-nitrophenyl)propane was dissolved in methanol (50 mL) andto the solution was added 10% Pd—C. The reaction mixture was reactedunder hydrogen atmosphere (˜40 psi) for 1 h. The catalyst was filteredoff over celite. The filtrate was evaporated to give4-(3-fluoropropyl)analine.

4-(3-Fluoropropyl)aniline and 2,6-dichloro-5-fluoropyrimidine (1.5 g)were dissolved in methanol (5 mL) and water (1 mL). The reactionsolution was stirred at rt for 3 d. The reaction solution was dilutedwith water (100 mL) and extracted with ethyl acetate (2×100 mL). Theorganic layers were evaporated and purified by flash columnchromatography (EtOAc/hexanes=1/4, 1/2) to give2-chloro-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-4-pyrimidineamine.

2-Chloro-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-4-pyrimidineamine (100mg) and sulfanilamide (100 mg) were suspended in isopropanol (1 mL) andTFA (5 drops). The solution was heated at 100° C. overnight. Thesolution was evaporated and purified by flash column chromatography (2.0M NH₃/MeOH in dichloromethane=1-3%) and recrystallized from ethylacetate to giveN2-(4-aminosulfonylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-PYrimidinediamine.¹H NMR (DMSO-d₆): δ 1.89-2.02 (m, 2H), 2.67 (t, J=8.1 Hz, 2H), 4.38 (t,J=5.7 Hz, 1H), 4.53 (t, J=5.7 Hz, 1H), 7.11 (br, 2H), 7.19 (d, J=8.1 Hz,2H), 7.60 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.7 Hz,2H), 8.12 (d, J=3.9 Hz, 1H), 9.38 (br, 1H), 9.57 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.79; LCMS: purity: 91.96%; MS (m/e): 420.74 (MH⁺).

The following compounds were made in a similar fashion to the the aboveexample or by methods described herein or known to skilled artisans.

VI-83:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.88-2.01 (m, 2H), 2.65 (t, J=7.8 Hz, 2H), 4.37 (t,J=6.0 Hz, 1H), 4.52 (t, J=6.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.24 (br,2H), 7.37 (m, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.95 (d, J=7.8 Hz, 1H), 8.09(d, J=3.3 Hz, 2H), 9.32 (br, 1H), 9.48 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.10; LCMS: purity: 93.78%; MS (m/e): 420.78 (MH⁺).

VI-84:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.88-1.98 (m, 2H), 2.65 (t, J=7.8 Hz, 2H), 4.36 (t,J=6.0 Hz, 1H), 4.52 (t, J=6.0 Hz, 1H), 7.17 (m, 5H), 7.70 (d, J=8.1 Hz,2H), 7.88 (dd, J=2.4, 8.4 Hz, 1H), 8.05 (d, J=3.9 Hz, 1H), 8.10 (d,J=2.1 Hz, 1H), 9.27 (br, 1H), 9.37 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ −202.68; LCMS: purity: 97.85%; MS (m/e): 434.92 (MH⁺).

VI-85:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-hydroxypropyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.72 (p, J=7.2 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 3.42(t, J=6.3 Hz, 2H), 4.47 (br, 1H), 7.11 (br, 2H), 7.16 (d, J=8.4 Hz, 2H),7.60 (d, J=9.0 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H),8.11 (d, J=3.9 Hz, 1H), 9.36 (br, 1H), 9.57 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.84; LCMS: purity: 97.76%; MS (m/e): 418.20 (MH⁺).

VI-86:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-hydroxypropyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.71 (p, J=7.5 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H), 3.41(q, J=6.0 Hz, 2H), 4.44 (t, J=5.1 Hz, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.24(br, 2H), 7.34 (m, 2H), 7.67 (d, J=8.1 Hz, 2H), 7.95 (d, J=7.2 Hz, 1H),8.08 (d, J=3.6 Hz, 2H), 9.29 (br, 1H), 9.47 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.16; LCMS: purity: 89.77%; MS (m/e): 418.18 (MH⁺).

VI-87:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-hydroxypropyl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 94.51%; MS (m/e): 432.66 (MH⁺).

I-152:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.67 (d, J=4.8 Hz, 3H), 4.56 (s, 2H), 7.01 (d, J=9.0Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.47 (br, 2H), 7.69 (dd, J=2.7, 8.7 Hz,1H), 7.80 (d, J=2.4 Hz, 1H), 7.88 (br, 1H), 8.02 (dd, J=2.7, 8.7 Hz,1H), 8.12 (d, J=3.9 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H), 9.51 (br, 1H), 9.72(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.67; LCMS: purity: 91.37%;MS (m/e): 515.31 (MH⁺).

I-140:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.85 (s, 3H), 3.01 (s, 3H), 4.93 (s, 2H), 6.96 (d,J=9.0 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 7.46 (br, 2H), 7.61 (dd, J=2.4,9.0 Hz, 1H), 7.72 (d, J=2.7 Hz, 1H), 8.01 (dd, J=2.7, 9.0 Hz, 1H), 8.10(d, J=3.6 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H), 9.43 (br, 1H), 9.67 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.04; LCMS: purity: 91.74%; MS (m/e):529.35 (MH⁺).

I-141:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-dimethylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.13 (s, 3H), 2.87 (s, 3H), 3.01 (s, 3H), 4.97 (s,2H), 7.00 (d, J=8.7 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.54 (br, 2H), 7.58(d, J=2.4 Hz, 1H), 7.88 (m, 2H), 7.96 (s, 1H), 9.26 (br, 1H), 10.12 (br,1H); LCMS: purity: 97.43%; MS (m/e): 525.37 (MH⁺).

I-142:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(4-dimethylaminocarbonylmethoxy-3-fluorophenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.14 (s, 3H), 2.86 (s, 3H), 3.00 (s, 3H), 4.94 (s,2H), 7.04 (t, J=9.3 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.45 (d, J=9.0 Hz,1H), 7.46 (dd, 1H), 7.55 (br, 2H), 7.89 (m, 2H), 7.96 (s, 1H), 9.39 (br,1H), 10.26 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −172.86; LCMS:purity: 99.33%; MS (m/e): 509.19 (MH⁺).

I-153:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.09 (s, 3H), 2.68 (d, J=4.5 Hz, 3H), 4.56 (s, 2H),7.00 (d, J=9.0 Hz, 1H), 7.35 (d, J=9.0 Hz, 1H), 7.43 (br, 2H), 7.67 (d,J=8.7 Hz, 1H), 7.71 (s, 1H), 7.89 (s, 2H), 8.07 (d, J=8.7 Hz, 1H), 8.21(s, 1H), 8.33 (s, 1H), 9.44 (br, 1H); LCMS: purity: 98.98%; MS (m/e):511.34 (MH⁺).

VI-88:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-hydroxybutyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.44 (m, 2H), 1.60 (m, 2H), 2.57 (t, J=7.5 Hz, 2H),3.41 (q, J=6.0 Hz, 2H), 4.37 (t, J=5.1 Hz, 1H), 7.11 (br, 2H), 7.16 (d,J=8.7 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.80 (d,J=9.0 Hz, 2H), 8.11 (d, J=3.6 Hz, 1H), 9.36 (br, 1H), 9.57 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.84; LCMS: purity: 90.99%; MS (m/e):432.24 (MH⁺).

VI-89:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-hydroxybutyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.43 (m, 2H), 1.59 (m, 2H), 2.55 (t, J=7.5 Hz, 2H),3.40 (q, J=5.8 Hz, 2H), 4.36 (t, J=4.8 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H),7.21 (br, 2H), 7.33 (m, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.95 (d, J=6.9 Hz,1H), 8.08 (d, J=3.9 Hz, 2H), 9.29 (br, 1H), 9.47 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −202.14; LCMS: purity: 92.80%; MS (m/e): 432.24 (MH⁺).

VI-90:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-hydroxybutyl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 91.08%; MS (m/e): 446.51 (MH⁺).

VI-91:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-fluorobutyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.64-1.69 (m, 4H), 2.62 (t, J=6.9 Hz, 2H), 4.38 (t,J=5.7 Hz, 1H), 4.54 (t, J=6.0 Hz, 1H), 7.11 (br, 2H), 7.18 (d, J=8.7 Hz,2H), 7.60 (d, J=9.3 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.80 (d, J=9.0 Hz,2H), 8.12 (d, J=3.9 Hz, 1H), 9.37 (br, 1H), 9.58 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.85; LCMS: purity: 89.65%; MS (m/e): 434.59 (MH⁺).

VI-92:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-fluorobutyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ1.64-1.68 (m, 4H), 2.59 (t, J=6.9 Hz, 2H), 4.37 (t,J=6.3 Hz, 1H), 4.53 (t, J=5.4 Hz, 1H), 7.15 (d, J=8.1 Hz, 2H), 7.24 (br,2H), 7.34 (m, 2H), 7.68 (d, J=7.8 Hz, 2H), 7.95 (d, J=7.2 Hz, 1H), 8.08(d, J=2.4 Hz, 2H), 9.30 (br, 1H), 9.47 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.13; LCMS: purity: 91.90%; MS (m/e): 434.60 (MH⁺).

VI-93:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-fluorobutyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ1.63-1.68 (m, 4H), 2.60 (t, J=6.9 Hz, 2H), 4.37 (t,J=5.7 Hz, 1H), 4.53 (t, J=5.1 Hz, 1H), 7.16 (d, J=8.7 Hz, 2H), 7.18 (d,J=8.1 Hz, 1H), 7.26 (br, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.80 (d, J=7.5 Hz,1H), 7.98 (s, 1H), 8.13 (d, J=4.5 Hz, 1H), 9.75 (br, 2H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.39; LCMS: purity: 84.96%; MS (m/e): 448.68 (MH⁺).

I-154:N2-(4-Aminosulfonylphenyl)-N4-(3-fluoro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.66 (d, J=4.2 Hz, 3H), 4.58 (s, 2H),7.10 (t, J=9.0 Hz, 1H), 7.26 (br, 3H), 7.57 (dd, J=2.4, 12.9 Hz, 1H),7.61 (d, J=8.7 Hz, 2H), 7.66 (d, J=9.3 Hz, 2H), 7.93 (s, 1H), 8.02 (d,J=3.9 Hz, 1H), 9.59 (br, 1H), 10.44 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −171.80; LCMS: purity: 99.32%; MS (m/e): 461.58 (MH⁺).

I-155:N2-(3-Aminosulfonylphenyl)-N4-(3-fluoro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 2.66 (d, J=4.5 Hz, 3H), 4.56 (s, 2H),7.06 (t, J=9.3 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.34 (br, 2H), 7.40 (t,J=7.8 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.53 (d, J=12.0 Hz, 1H), 7.72 (s,1H), 7.84 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.98 (d, 1H), 9.50 (br, 1H),10.26 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −171.83; LCMS: purity:99.44%; MS (m/e): 461.52 (MH⁺).

I-156:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-fluoro-4-methylaminocarbonylmethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.14 (s, 3H), 2.54 (s, 3H), 2.65 (d, J=4.8 Hz, 3H),4.56 (s, 2H), 7.06 (t, J=9.0 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 7.28 (d,J=8.4 Hz, 1H), 7.36 (br, 2H), 7.51 (dd, J=10.8 Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.72 (s, 1H), 7.86 (s, 1H), 7.99 (d, 1H), 9.58 (br, 1H), 10.35(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −171.83; LCMS: purity: 98.38%;MS (m/e): 475.67 (MH⁺).

III-32:N4-(4-Aminocarbonylaminomethylphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.17 (s, 2H), 6.47 (br, 1H), 7.17 (br, 2H), 7.23 (d,J=8.7 Hz, 2H), 7.62 (d, J=9.0 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.77 (d,J=9.0 Hz, 2H), 8.15 (d, J=3.9 Hz, 1H), 9.60 (br, 1H), 9.73 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.32; LCMS: purity: 96.25%; MS (m/e):432.11 (MH⁺).

III-33:N4-(4-Aminocarbonylaminomethylphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.15 (s, 2H), 6.46 (br, 1H), 7.21 (d, J=8.1 Hz, 2H),7.28 (br, 2H), 7.39 (d, J=4.8 Hz, 2H), 7.67 (d, J=7.5 Hz, 2H), 7.92 (m,1H), 8.01 (s, 1H), 8.15 (d, J=3.6 Hz, 1H), 9.68 (br, 1H), 9.75 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.24; LCMS: purity: 95.09%; MS (m/e):432.51 (MH⁺).

III-34:N4-(4-Aminocarbonylaminomethylphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.52 (s, 3H), 4.15 (s, 2H), 6.42 (br, 1H), 7.20 (d,J=8.4 Hz, 1H), 7.21 (d, J=8.1 Hz, 2H), 7.26 (br, 2H), 7.66 (d, J=8.4 Hz,2H), 7.83 (d, J=8.1 Hz, 1H), 8.01 (s, 1H), 8.13 (d, J=4.2 Hz, 1H), 9.70(br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.66; LCMS: purity: 85.70%;MS (m/e): 446.65 (MH⁺).

IX-41:N4-(4-Acetylthiomethylcarbonylphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.36 (s, 3H), 4.11 (s, 2H), 7.15 (br, 2H), 7.27 (d,J=8.4 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.76 (d,J=9.0 Hz, 2H), 8.18 (d, J=3.9 Hz, 1H), 9.69 (br, 1H), 9.81 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −200.96; LCMS: purity: 78.34%; MS (m/e):448.42 (M-28).

IX-42:N4-(4-Acetylthiomethylcarbonylphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.35 (s, 3H), 4.09 (s, 2H), 7.24 (d, J=8.4 Hz, 2H),7.25 (br, 2H), 7.36 (m, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.91 (m, 1H), 8.05(s, 1H), 8.13 (d, J=3.6 Hz, 1H), 9.53 (br, 1H), 9.60 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ −201.56; LCMS: purity: 84.49%; MS (m/e): 448.41(M-28).

IX-43:N4-(4-Acetylthiomethylcarbonylphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.36 (s, 3H), 4.10 (s, 2H), 7.20 (d, J=8.1 Hz, 1H),7.25 (d, J=8.4 Hz, 2H), 7.28 (br, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.79 (dd,J=2.4, 8.4 Hz, 1H), 7.96 (s, 1H), 8.17 (d, J=4.2 Hz, 1H), 9.86 (br, 1H),9.89 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.03; LCMS: purity:85.44%; MS (m/e): 462.21 (M-28).

III-44:N4-(4-Acrylamidomethylphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.33 (d, J=6.0 Hz, 2H), 5.61 (dd, J=2.4, 9.9 Hz,1H), 6.11 (dd, J=2.4, 17.1 Hz, 1H), 6.27 (dd, J=9.6, 17.1 Hz, 1H), 7.12(br, 2H), 7.23 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.1Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 8.13 (d, J=3.6 Hz, 1H), 8.59 (t, J=5.7Hz, 1H), 9.43 (br, 1H), 9.58 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.60; LCMS: purity: 93.70%; MS (m/e): 443.22 (MH⁺).

III-45:N4-(4-Acrylamidomethylphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.32 (d, J=6.0 Hz, 2H), 5.61 (dd, J=2.1, 9.9 Hz,1H), 6.11 (dd, J=2.4, 17.1 Hz, 1H), 6.28 (dd, J=10.2, 17.4 Hz, 1H), 7.22(d, J=8.1 Hz, 2H), 7.25 (br, 2H), 7.34 (m, 2H), 7.74 (d, J=8.4 Hz, 2H),7.95 (d, J=7.5 Hz, 1H), 8.10 (s, 1H), 8.10 (d, J=3.6 Hz, 1H), 8.57 (t,1H), 9.38 (br, 1H), 9.49 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−202.04; LCMS: purity: 91.76%; MS (m/e): 443.57 (MH⁺).

III-46:N4-(4-Acrylamidomethylphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.32 (d, J=6.3 Hz, 2H), 5.61 (dd, J=2.4, 9.9 Hz,1H), 6.12 (dd, J=2.4, 17.1 Hz, 1H), 6.28 (dd, J=9.9, 17.1 Hz, 1H), 7.15(d, J=8.1 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.22 (br, 2H), 7.74 (d, J=8.4Hz, 2H), 7.89 (dd, J=2.1, 8.1 Hz, 1H), 8.07 (d, J=3.9 Hz, 1H), 8.10 (d,J=2.1 Hz, 1H), 8.56 (t, J=5.4 Hz, 1H), 9.34 (br, 1H), 9.38 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −202.59; LCMS: purity: 88.19%; MS (m/e):457.48 (MH⁺).

IX-15:N2-(3-Aminosulfonylphenyl)-N4-(3-cyanomethyl-1H-indol-7-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.07 (s, 1H), 7.88 (s, 1H), 7.50 (d, 1H, J=8.1 Hz),7.16 (m, 6H), 4.08 (s, 2H); LCMS: purity: 93%; MS (m/e): 438 (MH⁺).

IX-16:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-cyanomethyl-1H-indol-7-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.05 (d, 1H, J=3.3 Hz), 7.88 (s, 1H), 7.50 (d, 1H,J=7.5 Hz), 7.39 (d, 1H, J=7.8 Hz), 7.28 (s, 1H), 7.23 (d, 2H, J=7.8 Hz),7.07 (t, 1H, J=7.8 Hz), 6.75 (d, 1H, J=8.4 Hz), 4.08 (s, 2H), 2.39 (s,3H); LCMS: purity: 92%; MS (m/e): 452 (MH⁺).

I-9:N2-[3-Aminosulfonyl-4-(4-methylpiperazin-1-yl)phenyl]-5-fluoro-N4-(4-cyanomethyleneoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.07 (d, 1H, J=4.62 Hz), 7.95 (bs, 1H), 7.70 (bs,2H), 7.44 (d, 1H, J=9.3 Hz), 7.06 (d, 2H, J=9 Hz), 5.14 (s, 2H), 3.15(s, 4H), 2.90 (bs, 4H), 2.27 (s, 3H); LCMS: purity: 91%; MS (m/e): 514(MH⁺).

I-251:N2-[3-Aminosulfonyl-4-(4-methylpiperazin-1-yl)phenyl]-5-fluoro-N4-[2-fluoro-4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.07 (bs, 1H), 7.98 (d, 1H, J=9 Hz), 7.87 (d, 1H,J=13.8 Hz), 7.53 (d, 1H, J=9.3 Hz), 7.42 (d, 1H, J=8.7 Hz), 7.20 (t, 1H,J=9 Hz), 6.33 (s, 1H), 5.18 (s, 2H), 3.15 (s, 4H), 2.90 (s, 4H), 2.41(s, 3H), 2.28 (s, 3H); LCMS: purity: 98%; MS (m/e): 588 (MH⁺).

I-10:N2-[3-Aminosulfonyl-4-(4-methylpiperazine-1-yl)phenyl]-5-fluoro-N4-(4-cyanomethyleneoxy-3-fluorophenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.10 (t, 2H, J=3.6 Hz), 7.92 (m, 2H), 7.58 (d, 1H,J=3.3 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.26 (t, 1H, J=8.7 Hz), 5.19 (s, 2H),3.15 (s, 4H), 2.90 (s, 4H), 2.22 (s, 3H); LCMS: purity: 94%; MS (m/e):531 (MH⁺).

I-11:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-cyanomethyleneoxy-3-fluorophenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.10 (t, 2H, J=3.6 Hz), 7.92 (m, 2H), 7.59 (d, 1H,J=9.0 Hz), 7.24 (m, 2H), 5.20 (s, 2H), 2.45 (s, 3H); LCMS: purity: 94%;MS (m/e): 447 (MH⁺).

I-12:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-cyanomethyleneoxy-3-fluorophenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.13 (t, 1H, J=3.9 Hz), 8.10 (s, 1H), 7.95 (m, 2H),7.60 (d, 1H, J=8.7 Hz), 7.36 (m, 3H), 5.20 (s, 2H); LCMS: purity: 95%;MS (m/e): 433 (MH⁺).

IX-20:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-cyanomethyl-1-methyl-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.32 (s, 1H), 9.21 (s, 1H), 8.08 (s, 1H), 8.02 (d,1H, J=3.9 Hz), 7.89 (s, 2H), 7.46 (s, 1H), 7.34 (s, 1H), 7.21 (s, 2H),4.02 (s, 2H), 3.75 (s, 3H), 2.47 (s, 3H); LCMS: purity: 99%; MS (m/e):467 (MH⁺).

III-103:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-N-morpholinomethylenephenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.10 (m, 2H), 7.96 (m, 2H), 7.76 (d, 1H, J=8.1 Hz),7.35 (m, 1H), 7.25 (m, 2H), J=5.7 Hz), 3.57 (bs, 4H), 3.43 (bs, 2H),2.28 (bs, 4H); LCMS: purity: 96%; MS (m/e): 459 (MH⁺).

III-104:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-N-morpholinomethylenephenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.08 (t, 1H, J=3.6 Hz), 7.92 (d, 1H, J=8.1 Hz), 7.57(d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=7.5 Hz), 7.16 (d, 1H, J=8.1 Hz), 3.57(bs, 4H), 3.44 (s, 2H), 2.36 (s, 4H), 2.07 (s, 3H); LCMS: purity: 99%;MS (m/e): 473 (MH⁺).

III-105:N2-(3-Aminosulfonyl-4-methyleneoxyphenyl)-5-fluoro-N4-(4-N-morpholinomethylenephenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.05 (d, 1H, J=3.6 Hz), 7.98 (m, 1H), 7.89 (m, 1H),7.59 (d, 1H, J=8.4 Hz), 7.24 (d, 1H, J=8.1 Hz), 7.06 (m, 1H), 6.97 (s,2H), 3.85 (s, 3H), 3.56 (bs, 4H), 3.42 (s, 2H), 2.34 (bs, 4H); LCMS:purity: 95%; MS (m/e): 489 (MH⁺).

III-110:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[(1,1-dioxothiomorpholin-4-yl-)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.12 (d, 2H, J=3.6 Hz), 7.95 (m, 1H), 7.78 (d, 2H,J=8.4 Hz), 7.37 (m, 2H), 7.28 (d, 2H), 3.64 (s, 2H), 3.10 ((bs, 4H),2.87 (bs, 4H); LCMS: purity: 97%; MS (m/e): 507 (MH⁺).

III-111:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(1,1-dioxothiomorpholin-4-yl-)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.1 (d, 2H, J=2.4 Hz), 8.08 (d, 1H, J=3.9 Hz), 7.90(m, 1H), 7.78 (d, 2H, J=8.7 Hz), 7.22 (m, 3H), 3.64 (s, 2H), 3.10 (bs,4H), 2.45 (s, 3H), 2.88 (bm, 4H); LCMS: purity: 98%; MS (m/e): 521(MH⁺).

III-112:N2-(3-Aminosulfonyl-4-methyloxyphenyl)-5-fluoro-N4-{4-[(1,1-dioxothiomorpholin-4-yl-)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.06 (d, 1H, J=3.6 Hz), 7.99 (bs, 1H), 7.97 (m, 2H),7.28 (d, 2H, J=7.8 Hz), 7.08 (d, 1H, J=9 Hz), 6.96 (s, 1H), 3.85 (s,3H), 3.65 (s, 2H), 3.12 (s, 4H), 2.90 (s, 4H); LCMS: purity: 91%; MS(m/e): 537 (MH⁺).

III-107:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-thiomorpholinomethylenephenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.10 (m, 2H), 7.95 (m, 1H), 7.75 (d, 2H, J=8.4 Hz),7.36 (d, 2H, J=7.2 Hz), 7.24 (t, 2H, J=8.7 Hz), 3.46 (s, 2H), 2.6 (s,4H), 2.48 (s, 4H); LCMS: purity: 96%; MS (m/e): 475 (MH+).

III-108:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-thiomorpholinomethylenephenyl)-2,4-pyrimidinediamine

¹H NMR (DMSOd-6): δ 8.07 (t, 2H, J=5.1 Hz), 7.89 (dd, 1H, J=8.4 Hz,J=1.8 Hz), 7.50 (d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.16 (d, 1H,J=8.1 Hz), 3.46 (s, 2H), 2.6 (s, 4H), 2.49 (s, 3H), 2.48 (s, 4H); LCMS:purity: 88%; MS (m/e): 489 (MH⁺).

III-109:N2-(3-Aminosulfonyl-4-methyoxyphenyl)-5-fluoro-N4-(4-thiomorpholinomethylenephenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.08 (d, 1H, J=8.06 Hz), 7.87 (bs, 1H), 7.78 (bs,1H), 7.73 (d, 1H, J=8.1 Hz), 7.23 (d, 1H, J=8.1 Hz), 7.01 (s, 2H), 3.77(s, 3H), 3.45 (s, 2H), 2.60 (s, 4H), 2.21 (s, 4H); LCMS: purity: 99%; MS(m/e): 505 (MH⁺).

II-9:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(N-methylpyrrolidin-3-yloxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.07 (t., 2H, J=4.8 Hz), 7.94 (d, 1H, J=6.6 Hz),7.66 (d, 2H, J=8.4 Hz), 7.33 (d, 2H, J=7.5 Hz), 7.25 (s, 1H), 6.85 (d,2H, J=8.1 Hz), 4.83 (s, 1H), 2.76 (m, 2H), 2.62 (m, 2H), 2.35 (m, 2H),2.26 (s, 3H); LCMS: purity: 90%; MS (m/e): 446 (MH⁺)

II-10:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(N-methylpyrrolidin-3-yloxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSOd-6): δ 8.06 (m, 2H), 7.93 (d, 1H, J=6.9 Hz), 7.66 (d, 2H,J=9.3 Hz), 7.33 (m, 2H), 6.85 (d, 2H, J=9.0 Hz), 4.83 (s, 1H), 2.75 (m,2H), 2.62 (m, 2H), 2.49 (s, 3H), 2.35 (m, 2H), 2.25 (s, 3H); LCMS:purity: 90%; MS (m/e): 473 (MH⁺).

IX-27:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-methylpiperazin-1-ylcarbonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.53 (s, 1H), 9.46 (s, 1H), 8.12 (s, 2H), 7.89 (t,3H, J=9.0 Hz), 7.25 (m, 3H), 3.49 (s, 4H), 2.31 (s, 3H), 2.19 (s, 3H);LCMS: purity: 92%; MS (m/e): 500 (MH⁺).

IX-28:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-methylpiperazin-1-ylcarbonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 95.3 (s, 1H), 8.16 (d, 1H, J=11.4 Hz), 7.92 (d, 2H,J=8.1 Hz), 7.35 (m, 3H), 7.26 (s, 3 Hz), 3.49 (s, 4H), 2.2 (s, 3H);LCMS: purity: 86%; MS (m/e): 486 (MH⁺)

II-5:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{3-methyl-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2,4-pyrimidinediamine

¹H NMR (CD₃OD): δ 6.92 (d, J=2.4 Hz, 1H), 6.73 (d, J=3.9 Hz, 1H), 6.61(dd, J=2.4 and 8.4 Hz, 1H), 6.29 (dd, J=2.7 and 8.4 Hz, 1H), 6.23-6.20(m, 1H), 6.01 (d, J=8.4 Hz, 1H), 5.79 (d, J=8.7 Hz, 1H), 3.35-3.25 (m,1H), 1.69-1.56 (m, 2H), 1.46 (s, 3H), 1.38-1.27 (m, 2H), 1.21 (s, 3H),1.09 (s, 3H), 0.96-0.86 (m, 2H), 0.81-0.70 (m, 2H); LCMS: purity: 92%,MS (m/e): 501 (MH⁺).

II-6:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(1-methylpiperidin-4-yl)oxy]-3-trifluoromethylphenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.39 (s, 1H), 9.37 (s, 1H), 8.09-8.01 (m, 3H), 7.81(dd, J=2.4 and 8.7 Hz, 1H), 7.77 (d, J=2.7 Hz, 1H), 7.27-7.21 (m, 3H),7.11 (d, J=8.4 Hz, 1H), 4.62-4.51 (m, 1H), 2.57-2.42 (m, 5H), 2.28-2.00(m, 2H), 2.16 (s, 3H), 1.98-1.86 (m, 2H), 1.75-1.63 (m, 2H); LCMS:purity: 97%(m/e): 555 (MH⁺).

II-7:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.31 (s, 1H), 9.18 (s, 1H), 8.07 (d, J=2.4 Hz, 1H),8.02 (d, J=3.9 Hz, 1H), 7.85 (dd, J=2.7 and 8.4 Hz, 1H), 7.62 (d, J=8.7Hz, 2H), 7.21 (s, 2H), 7.13 (d, J=8.7 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H),4.34-4.25 (m, 1H), 2.65-2.57 (m, 2H), 2.49 (s, 3H), 2.17 (s, 3H),2.20-2.10 (m, 2H), 1.98-1.87 (m, 2H), 1.69-1.55 (m, 2H); LCMS: purity:95 MS (m/e): 487 (MH⁺).

II-3: RacemicN2-(3-aminosulfonyl-4-methylphenyl)-N4-{3-chloro-4-[(1-methylpiperidin-3-yl)oxy]phenyl}-5-fluoro-2,4-pyrimidinediamine

¹H NMR (CD₃OD): δ 8.04 (d, J=2.4 Hz, 1H), 7.89 (d, J=3.6 Hz, 1H), 7.76(dd, J=2.4 and 8.4 Hz, 1H), 7.71 (d, J=2.7 Hz, 1H), 7.55 (dd, J=2.7 and9.0 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.36-4.27(m, 1H), 3.03-2.95 (m, 1H), 2.71-2.64 (m, 1H), 2.59 (s, 3H), 2.32 (s,3H), 2.30-2.25 (m, 1H), 2.24-2.12 (m, 1H), 2.10-2.02 (m, 1H), 1.96-1.84(m, 1H), 1.72-1.48 (m, 2H); LCMS: purity: 90%(m/e): 522 (MH⁺).

II-4: RacemicN2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(1-methylpiperidin-3-yl)oxy]phenyl}-2,4-pyrimidinediamine

¹H NMR (CD₃OD): δ 8.05 (d, J=2.4 Hz, 1H), 7.83 (d, J=3.6 Hz, 1H), 7.71(dd, J=2.4 and 8.1 Hz, 1H), 7.51 (d, J=9.3 Hz, 2H), 7.11 (d, J=8.1 Hz,1H), 6.90 (d, J=9.0 Hz, 2H), 4.41-4.30 (m, 1H), 2.89-2.78 (m, 1H), 2.58(s, 3H), 2.35-2.18 (m, 5H), 2.00-1.80 (m, 3H), 1.68-1.46 (m, 2H); LCMS:purity: 96%(m/e): 487 (MH⁺).

II-8:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{3-chloro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.41 (s, 1H), 9.31 (bs, 1H), 8.07 (d, J=3.6 Hz, 1H),8.04 (d, J=2.1 Hz, 1H), 7.86 (dd, J=2.1 and 8.1 Hz, 1H), 7.80 (d, J=2.4Hz, 1H), 7.66 (dd, J=2.7 and 9.0 Hz, 1H), 7.23 (bs, 2H), 7.18-7.12 (m,2H), 4.43-4.35 (m, 1H), 2.64-2.55 (m, 2H), 2.50 (s, 3H), 2.24-2.14 (m,5H), 1.96-1.86 (m, 2H), 1.74-1.63 (m, 2H); LCMS: purity: 98%; MS (m/e):522 (MH⁺).

II-1: RacemicN2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{3-[(1-methylpiperidin-3-yl)oxy]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.40 (s, 1H), 9.27 (s, 1H), 8.09 (d, J=3.6 Hz, 1H),8.06 (d, J=2.4 Hz, 1H), 7.93 (dd, J=2.4 and 8.4 Hz, 1H), 7.57-7.49 (m,1H), 7.32 (t, J=2.1 Hz, 1H), 7.23 (s, 2H), 7.17 (dd, J=2.4 and 8.4 Hz,2H), 6.63 (dd, J=1.8 and 7.8 Hz, 1H), 4.36-4.24 (m, 1H), 2.94-2.84 (m,1H), 2.61-2.52 (m, 1H), 2.49 (s, 3H), 2.17 (S, 3H), 2.06-1.91 (m, 2H),1.76-1.63 (m, 1H), 1.58-1.42 (m, 1H), 1.40-1.19 (m, 2H); LCMS: purity:90%; (m/e): 487 (MH⁺).

II-2:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{3-[(1-methylpiperidin-4-yl)oxy]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.42 (s, 1H), 9.25 (s, 1H), 8.10-8.07 (m, 2H), 7.92(dd, J=2.4 Hz, 1H), 7.56-7.50 (m, 1H), 7.28 (t, J=1.8 Hz, 1H), 7.22 (s,2H), 7.20-7.15 (m, 4H), 6.63 (dd, J=2.4 and 8.1 Hz, 1H), 4.31-4.20 (m,1H), 2.67-2.55 (m, 2H), 2.50 (s, 3H), 2.15-2.05 (m, 2H), 1.98-1.86 (m,2H), 1.68-1.54 (m, 2H); LCMS: purity: 98%; MS (m/e): 487 (MH⁺).

VII-16:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(1,2,3,4-tetrahydroisoquin-7-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.35 (s, 1H), 9.19 (s, 1H), 8.07 (d, J=2.4 Hz, 1H),8.04 (d, J=3.3, 1H), 7.90 (dd, J=1.8 and 8.1 Hz, 1H), 7.46 (dd, J=2.1and 8.4 Hz, 1H), 7.42-7.38 (m, 1H), 7.22 (bs, 2H), 7.16 (d, J=8.4 Hz,1H), 6.99 (d, J=8.7 Hz, 1H), 5.74 (s, 1H), 3.81 (s, 2H), 2.95 (t, J=6.0Hz, 2H), 2.43 (s, 3H); LCMS: purity: 97%; MS (m/e): 429 (MH⁺).

VII-17:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[2-(methylaminocarbonyl)-1,2,3,4-tetrahydroisoquin-7-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.81-9.69 (m, 2H), 8.14 (d, J=4.5 Hz, 1H), 7.95 (d,J=1.5 Hz, 1H), 7.84 (dd, J=2.4 and 8.1 Hz, 1H), 7.51-7.44 (m, 2H), 7.27(s, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 4.43 (s, 2H),3.52 (t, J=5.7 Hz, 2H), 2.73 (t, J=5.7 Hz, 2H), 2.59 (s, 3H), 2.46 (s,3H); LCMS: purity: 92%; MS (m/e): 487 (MH⁺).

VII-18:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[2-(dimethylaminocarbonyl)-1,2,3,4-tetrahydroisoquin-7-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.72-9.63 (m, 2H), 8.13 (d, J=4.2 Hz, 1H), 7.97 (s,1H), 7.85 (dd, J=2.4 and 8.1 Hz, 1H), 7.57 (s, 1H), 7.48-7.44 (m, 1H),7.27 (s, 2H), 7.20 (d, J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 4.26 (s,2H), 3.39 (t, J=5.4 Hz, 2H), 2.81 (t, J=5.4 Hz, 2H), 2.78 (s, 6H), 2.46(s, 3H); LCMS: purity: 98%; MS (m/e): 501 (MH⁺).

VII-3: RacemicN2-(3-aminosulfonyl-4-methylphenyl)-N4-(1-benzyl-4-methylpiperidin-3-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (CDCl₃): δ 8.56 (d, J=2.1 Hz, 1H), 7.62 (d, J=3.6 Hz, 1H), 7.25(dd, J=2.1 and 8.4 Hz, 1H), 7.21-7.10 (m, 5H), 7.07 (d, J=8.1 Hz, 1H),5.81-5.70 (m), 5.35-5.22 (m), 4.46-4.37 (m), 3.47 (d, J=13.2 Hz), 3.35(d, J=13.2 Hz), 2.79-2.68 (m), 2.67-2.56 (m), 2.51 (s), 2.27 (d, J=11.1Hz), 2.14-2.00 (m), 1.85-1.69 (m), 1.49-1.38 (m), 1.24-1.15 (m),0.89-0.86 (m); LCMS: purity: 98%; MS (m/e): 485 (MH⁺).

VII-4: RacemicN2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-methylpiperidin-3-yl)-2,4-pyrimidinediamine

¹H NMR (CD₃OD): δ 8.67 (d, J=2.4 Hz, 1H), 7.75 (d, J=3.9 Hz, 1H), 7.43(dd, J=2.4 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 4.63-4.57 (m), 3.06-2.95(m), 2.94-2.88 (m), 2.74-2.63 (m), 2.49 (s), 2.14-2.00 (m), 1.66-1.55(m), 1.52-1.40 (m), 1.32-1.26 (m), 0.99-0.88 (m); LCMS: purity: 98%; MS(m/e): 395 (MH⁺).

VII-5: RacemicN2-(3-aminosulfonyl-4-methylphenyl)-N4-(1-cyanomethylenecarbonyl-4-methylpiperidin-3-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.30 (s, 1H), 8.53-8.48 (m, 1H), 8.24 (s, 1H), 7.89(d, J=3.9 Hz, 1H), 7.62-7.56 (m, 1H), 7.22-7.14 (m, 3H), 4.51-4.42 (m),4.21-4.14 (m), 4.10-4.02 (m), 3.99-3.90 (m), 3.66-3.52 (m), 3.35-3.28(m), 3.15-3.00 (m), 2.96-2.84 (m), 2.49 (s), 2.14-1.99 (m), 1.86-1.62(m), 1.53-1.40 (m), 0.87 (d, J=6.6 Hz); LCMS: purity: 99%; MS (m/e): 463(MH⁺).

VI-49:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(methylaminocarbonyloxymethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.72 (s, 1H), 9.66 (s, 1H), 8.16 (d, J=4.2 Hz, 1H),7.99 (s, 1H), 7.85 (dd, J=1.8 and 8.4 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H),7.68 (s, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.27 (s, 2H), 7.19 (d, J=8.1 Hz,1H), 7.12-7.04 (m, 2H), 4.98 (s, 2H), 2.57 (d, J=4.2 Hz, 3H), 2.50 (s,3H); LCMS: purity: 96%; MS (m/e): 461 (MH⁺).

VII-19:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[1-(methylaminocarbonyl)-1,2,3,4-tetrahydroquin-6-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.98-9.84 (m, 2H), 8.16 (d, J=4.8 Hz, 1H), 7.92-7.88(m, 1H), 7.81 (dd, J=2.1 and 8.1 Hz, 1H), 7.46-7.38 (m, 3H), 7.31 (s,2H), 7.24 (d, J=8.1 Hz, 1H), 6.60 (s, 1H), 3.55 (t, J=6.0 Hz, 2H), 2.64(s, 3H), 2.59 (t, J=6.0 Hz, 2H), 2.52 (s, 3H), 1.812 (t, J=6.0 Hz, 2H);LCMS: purity: 94%; MS (m/e): 487 (MH⁺).

VI-50:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-trifluoromethylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.70 (s, 1H), 9.49 (s, 1H), 8.17 (d, J=3.6 Hz, 1H),8.13 (s, 1H), 8.07 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.63 (d,J=8.5 Hz, 2H), 7.28-7.18 (m, 3H), 2.50 (s, 3H); LCMS: purity: 99%; MS(m/e): 442 (MH⁺).

VI-51:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-trifluoromethylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.74 (s, 1H), 9.61 (s, 1H), 8.21 (d, J=3.6 Hz, 1H),8.13 (s, 1H), 8.07 (d, J=8.7 Hz, 2H), 7.89 (d, J=7.8 Hz, 2H), 7.64 (d,J=8.78 Hz, 2H), 7.45-7.34 (m, 2H), 7.27 (s, 2H),; LCMS: purity: 99%; MS(m/e): 428 (MH⁺).

VI-52:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-hydroxymethylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.38 (s, 1H), 9.30 (s, 1H), 8.11 (d, J=2.4 Hz, 1H),8.07 (d, J=3.9 Hz, 1H), 7.90 (dd, J=2.4 and 8.4 Hz, 1H), 7.75 (d, J=8.4Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.23 (s, 2H), 7.177 (d, J=8.7 Hz, 1H),5.10 (t, J=5.7 Hz, 1H), 4.46 (d, J=5.7 Hz, 2H)2.50 (s, 3H); LCMS:purity: 95%; MS (m/e): 404 (MH⁺).

VI-53:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514g, 1.85 mmol), 3-(aminosulfonyl)-4-methylaniline (0.689 g, 3.70 mmol),and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH(6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reactionmixture was cooled to room temperature and diluted with 1N HCl (80 mL).N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamineVI-53) was isolated as a white solid by suction filtration (0.703 g). ¹HNMR (DMSO-d₆): δ 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H),7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H),7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H),3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH⁺).

VI-54:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-vinylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.42 (s, 1H), 9.40 (s, 1H), 8.12 (d, J=2.4 Hz, 1H),8.09 (d, J=3.3 Hz, 1H), 7.89 (dd, J=2.4 and 8.4 Hz, 1H), 7.82 (d, J=8.4Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.23 (s, 2H), 7.18 (d, J=8.4 Hz, 1H),7.23 (s, 2H), 7.18 (d, J=8.4 Hz, 1H), 6.69 (dd, J=10.8 and 17.4 Hz, 1H),5.73 (d, J=17.4 Hz, 1H), 5.16 (d, J=11.4 Hz, 1H), 2.50 (s, 3H); LCMS:purity: 96%; MS (m/e): 400 (MH⁺).

VI-55:N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.58 (s, 1H), 9.31 (s, 1H), 8.26 (d, J=2.4 Hz, 1H),8.06 (d, J=3.6 Hz, 1H), 8.02 (dd, J=2.4 and 9.0 Hz, 1H), 7.68 (d, J=8.7Hz, 2H), 7.45 (s, 2H), 7.39 (d, J=8.7 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H),4.78 (d, J=2.4 Hz, 2H), 3.55 (t, J=2.4 Hz, 1H),; LCMS: purity: 97%; MS(m/e): 449 (MH⁺).

VII-20:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(methylaminocarbonyl)-1,2,3,4-tetrahydroquin-6-yl]-2,4-pyrimidinediamine

¹H NMR (CD₃OD): δ 8.17 (t, J=1.5 Hz, 1H), 7.93 (d, J=3.9 Hz, 1H), 7.79(ddd, J=1.2, 2.4, and 8.1 Hz, 1H), 7.56 (dd, J=2.4 and 8.7 Hz, 1H),7.48-7.34 (m, 4H), 7.30 (d, J=9.0 Hz, 1H), 3.67 (t, J=6.3 Hz, 2H), 2.80(s, 3H), 2.73 (t, J=6.3 Hz, 2H), 1.91 (t, J=6.3 Hz, 2H),; LCMS: purity:99%; MS (m/e): 472 (MH⁺).

III-59:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[2-(methylaminocarbonyloxy)ethyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.44 (s, 1H), 9.37 (s, 1H), 8.10-8.05 (m, 2H), 7.87(dd, J=2.1 and 8.1 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.22 (s, 2H),7.21-7.14 (m, 3H), 6.96-6.90 (m, 1H), 4.13 (t, J=6.6 Hz, 2H), 2.82 (t,J=6.6 Hz, 2H), 2.54 (d, J=4.5 Hz, 3H), 2.50 (s, 3H); LCMS: purity: 94%;MS (m/e): 476 (MH⁺).

III-60:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[2-(methylaminocarbonyloxy)ethyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.85 (s, 1H), 9.75 (s, 1H), 8.17 (d, J=3.9 Hz, 1H),7.98 (s, 1H), 7.93-7.87 (m, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.42-7.38 (m,2H), 7.29 (s, 2H), 7.21 (d, J=7.8 Hz, 2H), 6.97-6.90 (m, 1H), 4.13 (t,J=6.6 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H), 2.54 (d, J=3.6 Hz, 3H); LCMS:purity: 98%; MS (m/e): 461 (MH⁺).

III-61:N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-{4-[2-(methylaminocarbonyloxy)ethyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.60 (s, 1H), 9.36 (s, 1H), 8.29 (d, J=2.7 Hz, 1H),8.10 (d, J=3.3 Hz, 1H), 8.03 (dd, J=2.4 and 9.0 Hz, 1H), 7.70 (d, J=8.1Hz, 2H), 7.45 (s, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.20 (d, J=8.1 Hz, 2H),6.96-6.90 (m, 1H), 4.13 (t, J=7.2 Hz, 2H), 2.83 (t, J=6.9 Hz, 2H), 2.54(d, J=4.5 Hz, 3H); LCMS: purity: 95%; MS (m/e): 496 (MH⁺).

III-56:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-{4-[2-(dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.71 (bs, 2H), 8.13 (d, J=4.2 Hz, 1H), 8.01 (s, 1H),7.81 (dd, J=1.8 and 7.8 Hz, 1H), 7.66 (d, J=8.1 Hz, 2H), 7.27 (s, 2H),7.24-7.16 (m, 3H), 4.15 (t, J=6.6 Hz, 2H), 2.86 (t, J=6.6 Hz, 2H), 2.78(s, 6H), 2.51 (s, 3H); LCMS: purity: 98%; MS (m/e): 490 (MH⁺).

III-57:N2-(3-Aminosulfonylphenyl)-N4-{4-[2-(dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.77 (s, 1H), 9.67 (s, 1H), 8.16 (d, J=4.2 Hz, 1H),8.01 (s, 1H), 7.94-7.86 (m, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.41-7.36 (m,2H), 7.29 (s, 2H), 7.21 (d, J=8.7 Hz, 2H), 4.14 (t, J=6.6 Hz, 2H), 2.85(t, J=6.6 Hz, 2H), 2.79 (s, 6H); LCMS: purity: 97%; MS (m/e): 475 (MH⁺).

III-58:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-{4-[2-(dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.87 (s, 1H), 9.68 (s, 1H), 8.20 (d, J=2.7 Hz, 1H),8.16 (d, J=4.2 Hz, 1H), 7.97 (dd, J=2.7 and 8.7 Hz, 1H), 7.66 (d, J=8.4Hz, 2H), 7.49 (s, 2H), 7.42 (d, J=9.0 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H),4.15 (t, J=6.6 Hz, 2H), 2.86 (t, J=6.6 Hz, 2H), 2.78 (s, 6H); LCMS:purity: 98%; MS (m/e): 510 (MH⁺).

III-53:N4-{4-[2-(Aminocarbonyloxy)ethyl]phenyl}-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.00 (s, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.93 (d,J=2.1 Hz, 1H), 7.77 (dd, J=2.1 and 8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H),7.30 (s, 2H), 7.22 (d, J=8.4 Hz, 3H), 6.44 (bs, 2H), 4.10 (t, J=6.6 Hz,2H), 2.84 (t, J=6.6 Hz, 2H), 2.53 (s, 3H); LCMS: purity: 96%; MS (m/e):461(MH⁺).

III-54:N4-{4-[2-(Aminocarbonyloxy)ethyl]phenyl}-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.77 (s, 1H), 9.67 (s, 1H), 8.16 (d, J=4.2 Hz, 1H),8.01 (s, 1H), 7.96-7.89 (m, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.44-7.36 (m,2H), 7.29 (s, 2H), 7.21 (d, J=8.1 Hz, 2H), 4.09 (t, J=6.6 Hz, 2H), 2.83(t, J=6.6 Hz, 2H); LCMS: purity: 93%; MS (m/e): 447 (MH⁺).

III-55:N4-{4-[2-(Aminocarbonyloxy)ethyl]phenyl}-N2-(3-aminosulfonyl-4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.76 (s, 1H), 9.56 (s, 1H), 8.24 (d, J=2.4 Hz, 1H),8.13 (d, J=3.9 Hz, 1H), 7.99 (dd, J=2.4 and 8.7 Hz, 1H), 7.68 (d, J=8.7Hz, 2H), 7.48 (s, 2H), 7.43 (d, J=9.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H),4.10 (t, J=6.6 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H); LCMS: purity: 97%; MS(m/e): 482 (MH⁺).

III-56:5-Fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 12.01 (s, 1H), 9.44 (s, 1H), 9.26 (s, 1H), 8.16 (d,J=2.4 Hz, 1H), 8.06 (dd, J=0.3 and 3.3 Hz, 1H), 8.00 (dd, J=2.1 and 7.8Hz, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.7Hz, 2H), 4.77 (d, J=2.1 Hz, 2H), 3.56 (t, J=2.1 Hz, 1H), 2.49 (s, 3H),2.24 (q, J=7.2 Hz, 2H), 0.89 (t, J=7.2 Hz, 3H); LCMS: purity: 98%; MS(m/e): 484 (MH⁺).

VI-57:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.45 (s, 1H), 9.35 (s, 1H), 8.12-8.07 (m, 2H), 7.93(dd, J=2.1 and 8.4 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.42 (t, J=2.1 Hz,1H), 7.27-7.16 (m, 4H), 6.69 (dd, J=2.7 and 8.7 Hz, 1H), 4.77 (d, J=2.4Hz, 2H), 3.58 (t, J=2.4 Hz, 1H), 2.49 (s, 3H); LCMS: purity: 98%; MS(m/e): 428 (MH⁺).

VI-58:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-methyl-4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.09-9.90 (m, 2H), 8.17 (d, J=4.5 Hz, 1H), 7.87 (s,1H), 7.80 (dd, J=2.1 and 8.4 Hz, 1H), 7.49-7.42 (m, 2H), 7.32 (s, 2H),7.20 (d, J=8.1 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 4.81 (d, J=2.1 Hz, 2H),3.57 (t, J=2.1 Hz, 1H), 2.52 (s, 3H), 2.13 (s, 3H); LCMS: purity: 99%;MS (m/e): 442 (MH⁺).

VI-59:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-chloro-4-(prop-2-ynyloxy)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.06 (s, 1H), 8.22 (d, J=4.5 Hz, 1H), 7.89 (d,J=2.1 Hz, 1H), 7.82-7.75 (m, 2H), 7.65 (dd, J=2.4 and 9.0 Hz, 1H), 7.32(s, 2H), 7.24 (d, J=8.1 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 4.90 (d, J=2.1Hz, 2H), 3.63 (t, J=2.1 Hz, 1H), 2.52 (s, 3H); LCMS: purity: 99%; MS(m/e): 463 (MH⁺).

VI-60:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.94 (s, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.96 (s, 1H),7.82 (d, J=8.4 Hz, 1H), 7.75 (d, J=13.2 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H),7.31 (s, 2H), 7.23 (d, J=7.8 Hz, 1H), 7.17 (d, J=9.6 Hz, 1H), 4.88-4.86(m, 2H), 3.64-3.61 (m, 1H), 2.53 (s, 3H); LCMS: purity: 98%; MS (m/e):446 (MH⁺).

VI-61:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(but-2-ynyloxy)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.10 (s, 2H), 8.19 (d, J=4.8 Hz, 1H), 7.90 (d,J=2.1 Hz, 1H), 7.73 (dd, J=1.8 and 8.1 Hz, 1H), 7.57 (d, J=9.0 Hz, 2H),7.32 (s, 2H), 7.23 (d, J=8.1 Hz, 1H), 6.95 (d, J=9.0 Hz, 2H), 4.74-4.70(m, 2H), 2.53 (s, 3H), 1.83 (t, J=2.1 Hz, 3H); LCMS: purity: 98%; MS(m/e): 442 (MH⁺).

VIII-2:N4-(3-Chloro-4-cyanomethyleneoxyphenyl)-5-fluoro-N2-(5-methyl-2H-1,1-dioxide-1,2,4-benzothiadiazin-7-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 11.50 (bs, 1H), 9.57 (s, 1H), 8.17 (d, 1H, J=2.7Hz), 8.04 (s, 1H), 7.88 (d, 1H), 7.79 (m, 2H), 7.57 (dd, 1H, J=1.2 and9.0 Hz), 7.27 (t, 1H, J=9.6 Hz), 5.20 (s, 2H), 2.31 (s, 3H); LCMS:purity: 100%; MS (m/e): 472 (MH⁺).

VI-26:N2-(3-aminosulfonylphenyl)-5-bromo-N4-(3-chloro-4-methoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.61 (s, 1H), 8.64 (s, 1H), 8.21 (s, 1H), 7.91 (m,2H), 7.63 (d, 1H, J=2.7 Hz), 7.53 (dd, 1H, J=2.4 and 6.3 Hz), 7.30 (m,3H), 7.13 (d, 1H, J=9.3 Hz), 3.86 (s, 3H); LCMS: purity: 100%, MS (m/e):484 (M⁺), 486 (M+2).

VI-27:N2-(3-aminosulfonyl-4-methylphenyl)-5-bromo-N4-(3-chloro-4-methoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 10.01 (s, 1H), 9.15 (s, 1H), 8.28 (s, 1H), 7.84 (s,1H), 7.72 (dd, 1H, J=1.8 and 8.4 Hz), 7.61 (d, 1H, J=2.4 Hz), 7.47 (dd,1H, J=2.1 and 9.0 Hz), 7.29 (bs, 2H), 7.12 (m, 2H), 3.86 (s, 3H); LCMS:purity: 97%, MS (m/e): 498 (M⁺), 500 (M+2).

VI-28:N2-(3-Aminosulfonylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-trimethylsilylacetylene-2,4-pyrimidinediamine

LCMS: purity: 98%, MS (m/e): 502 (M⁺).

VII-82: (1R,2R,3S,4S)N4-(3-Aminocarbonylbicyclo[2.2.1]hept-5-en-2-yl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.30 (s, 1H), 8.19 (d, 1H, J=1.5 Hz), 7.88 (m, 2H),7.68 (bs, 1H), 7.46 (bd, 1H, J=7.8 Hz), 7.19 (m, 4H), 6.30 (bs, 2H),4.13 (t, 1H, J=7.5 Hz), 2.85 (bs, 1H), 2.77 (bs, 1H), 2.53 (m, 1H), 2.12(d, 1H, J=8.4 Hz), 1.40 (d, 1H, J=8.1 Hz); LCMS: purity: 97%, MS (m/e):433 (MH⁺).

I-13:N2-(3-Aminosulfonylphenyl)-5-bromo-N4-(4-cyanomethyleneoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.91 (s, 1H), 9.02 (s, 1H), 8.27 (d, 1H, J=0.9 Hz),7.85 (m, 2H), 7.53 (d, 2H, 8.1 Hz), 7.34 (m, 4H), 7.07 (d, 2H, J=8.1Hz), 5.18 (s, 2H); LCMS: purity: 100%, MS (m/e): 475 (M⁺), 477 (M+2).

I-14:N2-(3-Aminosulfonyl-4-methylphenyl)-5-bromo-N4-(4-cyanomethyleneoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 10.05 (s, 1H), 9.23 (s, 1H), 8.28 (s, 1H), 7.82 (s,1H), 7.74 (dd, 1H, J=2.1 and 8.4 Hz), 7.51 (d, 2H, J=8.7 Hz), 7.29 (bs,2H), 7.11 (m, 3H), 5.11 (s, 2H), 2.45 (s, 3H); LCMS: purity: 98%, MS(m/e): 491 (M+2).

VI-29:N2-(3-Aminosulfonyl-4-methoxyphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.03 (s, 1H), 9.33 (s, 1H), 8.09 (s, 1H), 7.12 (d,1H, J=1.8 Hz), 7.07 (d, 1H, J=2.1 Hz), 7.01 (m, 2H), 6.80 (dd, 1H, J=1.2and 9.0 Hz), 6.60 (d, 1H, J=8.7 Hz), 4.22 (s, 3H), 4.15 (s, 3H); LCMS:purity: 99%, MS (m/e): 453 (M+).

I-15:N2-(3-Aminosulfonylphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-trimethylsilylacetylene-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.48 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.67 (m,2H), 7.29 (m, 3H), 7.07 (m, 3H), 6.82 (m, 2H), 4.91 (s, 2H), 0.00 (s,9H); LCMS: purity: 89%, MS (m/e): 494 (MH⁺).

VII-38:N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(2,2-difluoro-4H-benz[1,4]oxazin-3-on-6-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.55 (s, 1H), 9.29 (s, 1H), 8.10 (bd, 1H), 7.82 (bs,1H), 7.86 (bs, 1H), 7.57 (bd, 1H, J=8.1 Hz), 7.42 (bs, 2H), 7.25 (bd,1H, J=8.7 Hz), 7.02 (bs, 2H), 3.75 (s, 3H), 2.16 (s, 3H); LCMS: purity:88%, MS (m/e): 511 (MH⁺).

VI-30:N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.31 (bs, 2H), 8.06 (bd, 1H, J=3.6 Hz), 7.39 (m,4H), 7.11 (d, 1H, J=8.7 Hz), 7.02 (bs, 2H), 3.83 (s, 3H), 3.76 (s, 3H),2.18 (s, 3H); LCMS: purity: 100%, MS (m/e): 468 (M⁺).

VII-83: (1R,2R,3S,4S)N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-ene-2-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.20 (s, 1H), 7.96 (d, 1H, =2.1 Hz), 7.86 (d, 1H,J=3.3 Hz), 7.78 (d, 1H, J=2.1 Hz), 7.65 (bs, 1H), 7.40 (bdd, 1H, J=7.8Hz), 7.16 (bs, 1H), 6.98 (bs, 2H), 6.28 (bs, 2H), 4.16 (t, 1H, J=7.5Hz), 3.76 (s, 3H), 2.84 (s, 1H), 2.74 (s, 1H), 2.53 (m, 1H), 2.25 (s,3H), 2.13 (d, 1H, J=8.4 Hz), 1.39 (d, 1H, J=8.1 Hz); LCMS: purity: 100%,MS (m/e): 463 (MH⁺).

VI-31:N2-(3-Aminosulfonylpyrid-4-yl)-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 100%, MS (m/e): 425 (MH+).

II-19:N2-(3-Aminocarbonyl-5-methylphenyl)-5-fluoro-N2-[4-(1-methylpyrazol-3-yl)amidophenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 10.67 (s, 1H), 9.70 (s, 1H), 9.63 (s, 1H), 8.18 (d,1H, J=3.6 Hz), 8.11 (d, 1H, J=2.4 Hz), 7.97 (m, 4H), 7.90 (dd, 1H, J=2.4and 8.4 Hz), 7.58 (d, 1H, J=2.1 Hz), 7.27 (m, 2H), 7.24 (m, 1H), 6.58(d, 1H, J=2.1 Hz), 3.78 (s, 3H), 2.52 (s, 3H); LCMS: purity: 91%, MS(m/e): 497 (MH⁺).

II-20:N2-(3-Aminocarbonyl-5-methylphenyl)-5-fluoro-N2-[4-(1-ethylpyrazol-5-yl)amidophenyl)-2,4-pyrimidinediamine

LCMS: purity: 97%, MS (m/e): 511 (M+).

II-21:N2-(3-Aminocarbonyl-5-methylphenyl)-5-fluoro-N2-[4-(1-methylpyrazol-5-yl)amidophenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 10.21 (s, 1H), 9.91 (s, 1H), 9.77 (s, 1H), 8.22 (d,1H, J=2.4 Hz), 8.07 (s, 1H), 7.96 (m, 6H), 7.38 (d, 1H, J=1.5 Hz), 7.27(m, 3H), 6.23 (s, 1H), 2.52 (s, 3H), 2.49 (s, 3H); LCMS: purity: 96%, MS(m/e): 497 (M⁺).

II-22:N2-(3-Aminocarbonyl-5-methylphenyl)-5-fluoro-N2-[4-(1H-pyrazol-5-yl)amidophenyl)-2,4-pyrimidinediamine

LCMS: purity: 91%, MS (m/e): 483 (MH⁺).

VI-24:N2-(3-Aminosulfonylphenyl)-5-carboethoxy-N4-(N-carboethoxymethylene-N-3-chloro-4-methoxyphenyl)-2,4-pyrimidinediamine

LCMS: purity: 94%; MS (m/e): 564 (M⁺).

VI-25:N2-(3-Aminosulfonyl-4-methylphenyl)-5-carboethoxy-N4-(N-carboethoxymethylene-N-3-chloro-4-methoxyphenyl)-2,4-pyrimidinediamine

LCMS: purity: 97%, MS (m/e): 579 (MH⁺).

VIII-3:N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(5-methyl-2H-1,1-dioxo-1,2,4-benzothiadiazin-7-yl)-2,4-pyrimidinediamine

LCMS: purity: 96%, MS (m/e): 463 (M⁺).

VI-33:N2-(3-aminosulfonylphenyl)-5-fluoro-N4-(4-trofluoromethoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.57 (s, 1H), 9.55 (s, 1H), 8.15 (d, 1H, J=3.6 Hz),8.12 (bs, 1H), 7.92 (m, 3H), 7.36 (m, 6H); LCMS: purity: 98%, MS (m/e):444 (MH⁺).

VII-53:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(2-cyanobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.53 (s, 1H), 9.42 (s, 1H), 8.29 (d, 1H, J=1.8 Hz),8.10 (m, 2H), 7.90 (m, 2H), 7.69 (d, 1H, J=9.0 Hz), 7.23 (bs, 1H), 7.13(d, 1H, J=8.1 Hz), 7.10 (m, 2H), 5.23 (s, 2H), 2.37 (s, 3H); LCMS:purity: 97%, MS (m/e): 439 (MH⁺).

VI-32:N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-trofluoromethoxyphenyl)-2,4-pyrimidinediamine

LCMS: purity: 100%, MS (m/e): 458 (MH+).

I-263:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.61 (s, 1H), 9.36 (s, 1H), 8.11 (d, 1H,J=3.6 Hz), 7.82 (d, 2H, J=8.7 Hz), 7.66 (d, 2H, J=8.7 Hz), 7.58 (d, 2H,J=8.7 Hz), 7.15 (br s, 1H), 7.03 (d, 2H, J=8.7 Hz), 5.46 (s, 2H), 2.74(br s, 2H), 2.36 (m, 9H), 0.85 (t, 6H, J=6.6 Hz); LCMS (m/z): 571 (MH⁺).

I-280:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.32 (s, 1H), 9.21 (d, 1H, J=1.8 Hz), 8.02(d, 1H, J=3.9 Hz), 7.87 (dd, 1H, J=2.1 and 8.2 Hz), 7.68 (d, 2H, J=9.0Hz), 7.52 (s, 1H), 7.21 (s, 2H), 7.13 (m, 1H), 6.98 (d, 2H, J=8.7 Hz),5.08 (s, 2H), 2.65 (s, 3H), 2.48 (s, 3H); LCMS (m/z): 501 (MH⁺).

I-281:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.44 (s, 1H), 9.25 (s, 1H), 8.06 (d, 2H,J=3.9 Hz), 7.93 (m, 1H), 7.67 (d, 1H, J=9.0 Hz), 7.52 (s, 1H), 7.32 (m,2H), 7.24 (s, 2H), 6.99 (d, 2H, J=8.7 Hz), 5.08 (s, 2H), 2.66 (s, 3H);LCMS (m/z): 487 (MH⁺).

I-282:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(2-methylthiazol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.34 (s, 1H), 9.22 (s, 1H), 8.04 (d, 1H,J=3.6 Hz), 8.00 (d, 1H, J=1.8 Hz), 7.93 (dd, 1H, J=2.4 and 8.1 Hz), 7.67(d, 2H, J=9.0 Hz), 7.52 (s, 1H), 7.31 (q, 1H, J=5.1 Hz), 7.18 (d, 1H,J=8.4 Hz), 6.99 (d, 2H, J=9.0 Hz), 5.08 (s, 2H), 2.65 (s, 3H), 2.45 (s,3H), 2.41 (d, 3H, J=4.5 Hz); LCMS (m/z): 515 (MH⁺).

I-283:N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methylthizol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.46 (s, 1H), 9.26 (s, 1H), 8.06 (d, 2H,J=5.1 Hz), 7.99 (m, 1H), 7.66 (d, 2H, J=9.0 Hz), 7.52 (s, 1H), 7.36 (t,1H, J=8.1 Hz), 7.26 (m, 2H), 6.99 (d, 2H, J=9.0 Hz), 5.08 (s, 2H), 2.78(t, 2H, J=7.8 Hz), 2.65 (s, 3H), 2.37 (m, 6H), 0.84 (t, 6H, J=6.9 Hz);LCMS (m/z): 586 (MH⁺).

I-284:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methylthizol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.59 (s, 1H), 9.32 (s, 1H), 8.09 (d, 1H,J=3.6 Hz), 7.82 (d, 2H, J=9.0 Hz), 7.58 (m, 5H), 7.15 (br s, 1H), 7.01(d, 2H, J=9.0 Hz), 5.09 (s, 2H), 2.72 (br s, 2H), 2.65 (s, 3H), 2.38 (m,6H), 0.84 (t, 6H, J=6.9 Hz); LCMS (m/z): 586 (MH⁺).

I-265:N2-(3-Aminosulfonyl-4-chloro-5-methylphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.50 (s, 1H), 9.31 (s, 1H), 8.07 (m, 2H),8.00 (s, 1H), 7.67 (d, 2H, J=8.7 Hz), 7.40 (s, 2H), 7.00 (d, 2H, J=9.3Hz), 5.44 (s, 2H), 2.36 (s, 3H), 2.24 (s, 3H); LCMS (m/z): 520 (MH⁺).

I-285:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.57 (s, 1H), 9.34 (s, 1H), 8.09 (d, 1H,J=3.9 Hz), 7.79 (d, 2H, J=8.7 Hz), 7.63 (d, 2H, J=6.3 Hz), 7.60 (d, 2H,J=6.6 Hz), 7.54 (s, 1H), 7.13 (s, 2H), 7.02 (d, 2H, J=9.0 Hz), 5.09 (s,2H), 2.66 (s, 3H); LCMS (m/z): 487 (MH⁺).

III-70:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.47 (s, 1H), 9.36 (s, 1H), 8.44 (d, 2H,J=5.7 Hz), 8.09 (d, 1H, J=3.6 Hz), 8.07 (s, 1H), 7.93 (m, 1H), 7.71 (d,2H, J=8.4 Hz), 7.25 (m, 8H), 3.94 (s, 2H); LCMS (m/z): 451 (MH⁺).

III-74:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.35 (s, 1H), 9.31 (s, 1H), 8.44 (d, 2H,J=5.7 Hz), 8.07 (d, 1H, J=2.4 Hz), 8.06 (d, 1H, J=3.6 Hz), 7.87 (dd, 1H,J=2.4 and 8.1 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.20 (m, 5H), 7.09 (m, 2H),3.93 (s, 2H), 2.36 (s, 3H); LCMS (m/z): 465 (MH⁺).

III-75:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.37 (s, 1H), 9.33 (s, 1H), 8.44 (d, 2H,J=5.7 Hz), 8.07 (d, 1H, J=3.6 Hz), 7.98 (d, 1H, J=2.1), 7.93 (dd, 1H,J=2.1 and 8.4 Hz), 7.70 (d, 2H, J=8.1 Hz), 7.32 (q, 1H, J=4.8 Hz), 7.24(d, 2H, J=5.4 Hz), 7.19 (d, 2H, J=8.1 Hz), 7.11 (d, 1H, J=8.1 Hz), 3.94(s, 2H), 2.44 (s, 3H), 2.40 (d, 3H, J=5.1 Hz); LCMS (m/z): 479 (MH⁺).

III-71:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.58 (s, 1H), 9.42 (s, 1H), 8.45 (d, 2H,J=6.0 Hz), 8.13 (d, 1H, J=3.9 Hz), 7.79 (d, 2H, J=8.7 Hz), 7.67 (d, 2H,J=8.4 Hz), 7.61 (d, 2H, J=9.0 Hz), 7.24 (m, 4H), 7.14 (br s, 2H), 3.96(s, 2H); LCMS (m/z): 451 (MH⁺).

I-188:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.46 (s, 1H), 9.27 (s, 1H), 8.66 (s, 1H),8.53 (d, 1H, J=3.6 Hz), 8.06 (d, 2H, J=2.7 Hz), 7.93 (m, 1H), 7.86 (d,1H, J=8.1 Hz), 7.68 (d, 2H, J=9.0 Hz), 7.41 (dd, 1H, J=4.8 and 7.6 Hz),7.32 (m, 2H), 7.25 (s, 2H), 7.00 (d, 2H, J=9.3 Hz), 5.15 (s, 2H); LCMS(m/z): 467 (MH⁺).

I-189:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.30 (s, 1H), 9.27 (s, 1H), 8.66 (s, 1H),8.53 (d, 1H, J=3.6 Hz), 8.08 (d, 1H, J=1.5 Hz), 8.03 (d, 1H, J=3.6 Hz),7.86 (d, 2H, J=8.4 Hz), 7.69 (d, 2H, J=9.0 Hz), 7.42 (dd, 1H, J=5.1 and7.8 Hz), 7.22 (s, 1H), 7.11 (m, 2H), 6.99 (d, 2H, J=8.7 Hz), 5.15 (s,2H), 2.36 (s, 3H); LCMS (m/z): 481 (MH⁺).

I-190:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.29 (s, 1H), 9.18 (s, 1H), 8.60 (s, 1H),8.46 (d, 1H, J=4.5 Hz), 7.98 (d, 1H, J=3.6 Hz), 7.93 (s, 1H), 7.87 (d,1H, J=8.4 Hz), 7.80 (d, 1H, J=7.5 Hz), 7.62 (d, 2H, J=8.7 Hz), 7.35 (dd,1H, J=4.5 and 7.6 Hz), 7.26 (q, 1H, J=5.1 Hz), 7.10 (d, 1H, J=8.4 Hz),6.93 (d, 2H, J=8.7 Hz), 5.08 (s, 2H), 2.39 (s, 3H), 2.35 (d, 3H, J=4.8Hz); LCMS (m/z): 495 (MH⁺).

III-1:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-(4-cyanomethylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.41 (s, 2H), 8.11 (d, 1H, J=3.6 Hz), 8.02(d, 1H, J=2.1 Hz), 7.95 (dd, 1H, J=1.8 and 8.2 Hz), 7.82 (d, 2H, J=8.7Hz), 7.29 (d, 3H, J=8.4 Hz), 7.21 (d, 1H, J=8.1 Hz), 3.99 (s, 2H), 2.46(s, 3H), 2.42 (d, 3H, J=2.4 Hz); LCMS (m/z): 427 (MH⁺).

I-182:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.52 (s, 1H), 9.34 (s, 1H), 8.65 (d, 1H,J=1.8 Hz), 8.53 (dd, 1H, J=1.5 and 4.6 Hz), 8.12 (d, 1H, J=3.6 Hz), 8.08(s, 1H), 7.98 (d, 1H, J=7.8 Hz), 7.84 (d, 1H, J=7.8 Hz), 7.47 (s, 2H),7.41 (m, 1H), 7.32 (m, 2H), 7.24 (m, 3H), 6.75 (m, 1H), 5.13 (s, 2H);LCMS (m/z): 467 (MH⁺).

I-183:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.42 (s, 1H), 9.31 (s, 1H), 8.65 (d, 1H,J=2.1 Hz), 8.52 (dd, 1H, J=1.5 and 4.7 Hz), 8.09 (m, 2H), 7.93 (dd, 1H,J=2.7 and 8.4 Hz), 7.84 (d, 1H, J=7.5 Hz), 7.47 (m, 2H), 7.41 (dd, 1H,J=4.8 and 7.6 Hz), 7.21 (m, 3H), 7.14 (d, 1H, J=8.4 Hz), 6.73 (m, 1H),5.11 (s, 2H), 2.44 (s, 3H); LCMS (m/z): 481 (MH⁺).

I-184:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.42 (s, 1H), 9.33 (s, 1H), 8.64 (s, 1H),8.52 (d, 1H, J=4.5 Hz), 8.11 (d, 1H, J=3.6 Hz), 7.98 (d, 2H, J=8.1 Hz),7.83 (d, 1H, J=7.5 Hz), 7.47 (s, 2H), 7.41 (m, 1H), 7.31 (q, 1H, J=4.8Hz), 7.23 (t, 1H, J=8.1 Hz), 7.17 (d, 1H, J=8.1 Hz), 6.73 (d, 1H, J=9.0Hz), 5.10 (s, 2H), 2.49 (s, 3H), 2.41 (d, 3H, J=4.5 Hz),; LCMS (m/z):495 (MH⁺).

III-2:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-(4-cyanomethylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.67 (s, 1H), 9.52 (s, 1H), 8.16 (d, 1H,J=3.3 Hz), 7.85 (d, 2H, J=8.7 Hz), 7.79 (d, 2H, J=8.1 Hz), 7.61 (d, 2H,J=8.7 Hz), 7.31 (d, 2H, J=8.4 Hz), 7.16 (br s, 1H), 4.01 (s, 2H), 2.74(t, 2H, J=7.2 Hz), 2.36 (q, 6H, J=7.2 Hz), 0.85 (t, 6H, J=6.9 Hz); LCMS(m/z): 498 (MH⁺).

VII-55:N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-[4-(3-pyridinylmethyl)benzo[1,4]oxazin-7-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.41 (s, 1H), 9.07 (s, 1H), 8.56 (s, 1H),7.47 (d, 1H, J=3.9 Hz), 8.01 (m, 3H), 7.72 (d, 1H, J=8.1 Hz), 7.36 (dd,1H, J=4.5 and 7.6 Hz), 7.31-7.11 (m, 6H), 6.65 (d, 1H, J=8.7 Hz), 4.51(s, 2H), 4.25 (t, 2H, J=4.5 Hz), 3.39 (t, 2H, J=4.2 Hz); LCMS (m/z): 508(MH⁺).

VII-56:N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-[4-(3-pyridinylmethyl)benzo[1,4]oxazin-7-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.30 (s, 1H), 9.03 (s, 1H), 8.56 (s, 1H),8.46 (d, 1H, J=3.6 Hz), 8.05 (d, 1H, J=1.8 Hz), 7.98 (d, 1H, J=3.6 Hz),7.91 (dd, 1H, J=2.1 and 8.4 Hz), 7.71 (d, 1H, J=7.5 Hz), 7.35 (dd, 1H,J=4.5 and 9.7 Hz), 7.21 (s, 2H), 7.19-7.05 (m, 3H), 6.64 (d, 1H, J=8.7Hz), 4.49 (s, 2H), 4.24 (t, 2H, J=4.5 Hz), 3.37 (t, 2H, J=4.5 Hz), 2.47(s, 3H); LCMS (m/z): 522 (MH⁺).

I-185:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.64 (s, 1H), 9.42 (s, 1H), 8.64 (s, 1H),8.51 (d, 1H, J=4.5 Hz), 8.16 (d, 1H, J=3.6 Hz), 7.84 (m, 3H), 7.63 (d,2H, J=8.7 Hz), 7.42 (m, 3H), 7.26 (t, 1H, J=7.8 Hz), 7.13 (s, 2H), 6.77(d, 1H, J=8.1 Hz), 5.13 (s, 2H), LCMS (m/z): 467 (MH⁺).

I-186:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.69 (s, 1H), 9.43 (s, 1H), 8.64 (s, 1H),8.51 (d, 1H, J=4.5 Hz), 8.16 (d, 1H, J=3.6 Hz), 7.84 (m, 3H), 7.59 (d,2H, J=8.7 Hz), 7.40 (m, 3H), 7.26 (t, 1H, J=8.1 Hz), 7.18 (br s, 1H),6.78 (d, 1H, J=8.1 Hz), 5.13 (s, 2H), 2.72 (s, 2H), 2.37 (q, 6H, J=6.9Hz), 0.85 (t, 6H, J=6.9 Hz), LCMS (m/z): 566 (MH⁺).

I-160 942988:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.32 (s, 1H), 9.21 (s, 1H), 8.56 (d, 1H,J=4.5 Hz), 8.09 (d, 1H, J=2.1 Hz), 8.02 (d, 1H, J=3.6 Hz), 7.83 (m, 2H),7.68 (d, 2H, J=9.0 Hz), 7.50 (d, 1H, J=7.8 Hz), 7.33 (dd, 1H, J=5.1 and7.0 Hz), 7.21 (s, 2H), 7.12 (d, 1H, J=8.4 Hz), 6.98 (d, 1H, J=8.7 Hz),5.73 (s, 2H), 2.48 (s, 3H); LCMS (m/z): 481 (MH⁺).

I-191:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.61 (s, 1H), 9.34 (s, 1H), 8.66 (s, 1H),8.53 (d, 1H, J=3.9 Hz), 8.10 (d, 1H, J=3.6 Hz), 7.86 (d, 1H, J=9.3 Hz),7.81 (d, 2H, J=8.7 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.56 (d, 1H, J=9.0 Hz),7.41 (dd, 1H, J=5.1 and 7.8 Hz), 7.21 (br s, 1H), 7.02 (d, 2H, J=9.0Hz), 5.18 (s, 2H), 2.72 (bs s, 2H), 2.34 (m, 6H), 0.83 (t, 6H, J=7.5Hz),; LCMS (m/z): 566 (MH⁺).

III-66:N2-(3-Aminosulfonyl-4-methoxyphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.27 (s, 1H), 9.17 (s, 1H), 8.44 (d, 2H,J=4.2 Hz), 8.04 (d, 1H, J=3.9 Hz), 7.97 (s, 1H), 7.86 (d, 1H, J=8.7 Hz),7.72 (d, 2H, J=8.1 Hz), 7.24 (d, 2H, J=4.5 Hz), 7.19 (d, 2H, J=8.1 Hz),7.01 (d, 1H, J=9.0 Hz), 6.95 (s, 2H), 3.93 (s, 2H), 3.83 (s, 3H); LCMS(m/z): 481 (MH⁺).

III-67:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.47 (s, 1H), 9.36 (s, 1H), 8.44 (d, 2H,J=5.1 Hz), 8.09 (d, 1H, J=3.3 Hz), 8.05 (s, 1H), 7.98 (d, 1H, J=7.5 Hz),7.71 (d, 2H, J=7.8 Hz), 7.25 (m, 7H), 3.94 (s, 2H), 2.79 (t, 2H, J=7.2Hz), 2.37 (q, 6H, J=6.9 Hz), 0.85 (t, 6H, J=6.6 Hz); LCMS (m/z): 550(MH⁺).

I-161:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.33 (s, 1H), 9.23 (s, 1H), 8.57 (d, 1H,J=4.8 Hz), 8.04 (d, 1H, J=3.9 Hz), 8.01 (d, 1H, J=2.1 Hz), 7.93 (dd, 1H,J=2.4 and 8.1 Hz), 7.82 (m, 1H), 7.68 (d, 2H, J=8.7 Hz), 7.51 (d, 1H,J=7.8 Hz), 7.32 (m, 2H), 7.16 (d, 1H, J=8.4 Hz), 6.98 (d, 2H, J=8.7 Hz),5.17 (s, 2H), 2.46 (s, 3H), 2.42 (d, 3H, J=4.8 Hz); LCMS (m/z): 495(MH⁺).

I-162:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.43 (s, 1H), 9.25 (s, 1H), 8.57 (d, 1H,J=5.4 Hz), 8.06 (d, 2H, J=3.9 Hz), 7.93 (m, 1H), 7.82 (m, 1H), 7.68 (d,2H, J=9.0 Hz), 7.51 (d, 1H, J=7.8 Hz), 7.31 (m, 3H), 7.24 (s, 2H), 6.99(d, 2H, J=9.0 Hz), 5.17 (s, 2H); LCMS (m/z): 467 (MH⁺).

I-193:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.45 (s, 1H), 9.27 (s, 1H), 8.56 (d, 2H,J=5.7 Hz), 8.06 (d, 2H, J=3.6 Hz), 7.93 (d, 1H, J=7.2 Hz), 7.68 (d, 2H,J=8.7 Hz), 7.42 (d, 1H, J=6.0 Hz), 7.28 (m, 4H), 6.98 (d, 2H, J=8.7 Hz),5.18 (s, 2H); LCMS (m/z): 467 (MH⁺).

I-194:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.33 (s, 1H), 9.23 (s, 1H), 8.56 (d, 2H,J=4.8 Hz), 8.07 (d, 1H, J=1.8 Hz), 8.02 (d, 1H, J=3.9 Hz), 7.86 (dd, 1H,J=2.4 and 8.2 Hz), 7.68 (d, 2H, J=9.3 Hz), 7.42 (d, 2H, J=5.4 Hz), 7.22(s, 2H), 7.11 (d, 1H, J=8.4 Hz), 6.97 (d, 2H, J=9.3 Hz), 5.18 (s, 2H),2.48 (s, 3H); LCMS (m/z): 481 (MH⁺).

III-72:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.63 (s, 1H), 9.43 (s, 1H), 8.45 (d, 2H,J=6.0 Hz), 8.13 (d, 1H, J=3.6 Hz), 7.82 (d, 2H, J=8.7 Hz), 7.67 (d, 2H,J=8.4 Hz), 7.57 (d, 2H, J=8.7 Hz), 7.23 (t, 4H, J=9.3 Hz), 7.18 (br s,1H), 3.96 (s, 2H), 2.71 (t, 2H, J=6.0 Hz), 2.37 (q, 6H, J=6.9 Hz), 0.84(t, 6H, J=6.5 Hz); LCMS (m/z): 550 (MH⁺).

I-187:N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[3-(3-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.54 (s, 1H), 9.37 (s, 1H), 8.65 (d, 1H,J=1.8 Hz), 8.52 (dd, 1H, J=1.5 and 4.8 Hz), 8.13 (d, 1H, J=3.6 Hz), 8.05(d, 1H, J=1.2 Hz), 8.02 (m, 1H), 7.84 (m, 1H), 7.47 (m, 2H), 7.43-7.34(m, 2H), 7.31 (br s, 1H), 7.24 (m, 2H), 6.74 (dd, 1H, J=2.4 and 7.9 Hz),5.12 (s, 2H), 2.78 (br s, 2H), 2.35 (q, 6H, J=7.2 Hz), 0.84 (t, 6H,J=6.9 Hz); LCMS (m/z): 566 (MH⁺).

I-163:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.57 (s, 1H), 9.34 (s, 1H), 8.57 (d, 1H,J=4.5 Hz), 8.09 (d, 1H, J=3.6 Hz), 7.84 (d, 1H, J=7.5 Hz), 7.79 (d, 2H,J=8.7 Hz), 7.61 (t, 4H, J=6.6 Hz), 7.52 (d, 1H, J=7.8 Hz), 7.33 (t, 1H,J=8.7 Hz), 7.13 (s, 2H), 7.02 (d, 2H, J=9.0 Hz), 5.18 (s, 2H); LCMS(m/z): 467 (MH⁺).

I-164:N2-(3-Aminosulfonylpyrid-4-yl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.29 (s, 1H), 9.28 (s, 1H), 8.69 (d, 1H,J=7.5 Hz), 8.56 (m, 1H), 8.45 (d, 1H, J=3.3 Hz), 8.36 (s, 1H), 7.83 (m,1H), 7.58 (d, 2H, J=9.0 Hz), 7.52 (d, 1H, J=8.1 Hz), 7.34 (m, 1H), 7.06(d, 2H, J=9.0 Hz), 6.91 (d, 1H, J=7.8 Hz), 5.18 (s, 2H); LCMS (m/z): 468(MH⁺).

I-165:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

LCMS (m/z): 566 (MH⁺).

I-166:N2-[3-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.45 (s, 1H), 9.28 (s, 1H), 8.56 (d, 1H,J=4.5 Hz), 8.14 (s, 1H), 8.05 (m, 2H), 7.98 (d, 1H, J=8.4 Hz), 7.82 (m,1H), 7.67 (d, 2H, J=9.0 Hz), 7.51 (d, 1H, J=7.8 Hz), 7.33 (t, 2H, J=7.8Hz), 7.25 (d, 1H, J=7.8 Hz), 6.99 (d, 2H, J=8.7 Hz), 5.17 (s, 2H), 2.79(t, 2H, J=7.5 Hz), 2.38 (q, 6H, J=6.9 Hz), 0.85 (t, 6H, J=7.2 Hz); LCMS(m/z): 566 (MH⁺).

I-195:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(4-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.35 (s, 1H), 9.25 (s, 1H), 8.56 (d, 2H,J=4.5 Hz), 8.05 (d, 1H, J=2.4 Hz), 7.99 (s, 1H), 7.92 (d, 1H, J=7.8 Hz),7.68 (d, 2H, J=8.7 Hz), 7.43 (d, 2H, J=5.1 Hz), 7.33 (q, 1H, J=4.8 Hz),7.15 (d, 1H, J=7.8 Hz), 6.98 (d, 2H, J=7.8 Hz), 5.18 (s, 2H), 2.45 (s,3H), 2.41 (d, 3H, J=4.2 Hz); LCMS (m/z): 495 (MH⁺).

III-81:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.49 (s, 1H), 9.42 (s, 1H), 8.11 (m, 3H),7.93 (m, 1H), 7.77 (d, 3H, J=8.4 Hz), 7.25 (m, 6H), 6.89 (s, 1H), 5.14(s, 2H); LCMS (m/z): 440 (MH⁺).

III-82:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.38 (s, 2H), 8.14 (s, 1H), 8.08 (s, 2H),7.86 (dd, 1H, J=1.8 and 8.2 Hz), 7.78 (s, 1H), 7.74 (d, 2H, J=4.5 Hz),7.20 (m, 4H), 7.11 (d, 1H, J=8.1 Hz), 6.89 (d, 1H, J=0.9 Hz), 5.14 (s,2H), 2.49 (s, 3H); LCMS (m/z): 454 (MH⁺).

IX-33:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(4-thiomorpholino)carbonylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.52 (s, 1H), 9.47 (s, 1H), 8.14 (d, 1H,J=3.9 Hz), 8.05 (d, 1H, J=2.1 Hz), 7.92 (m, 3H), 7.34 (m, 3H), 7.23 (d,1H, J=8.1 Hz), 3.72 (br s, 4H), 2.64 (br s, 4H), 2.47 (s, 3H), 2.41 (d,3H, J=4.8 Hz); LCMS (m/z): 517 (MH⁺).

IX-34:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-thiomorpholinyl)carbonylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.59 (s, 1H), 9.57 (s, 1H), 8.17 (d, 1H,J=3.3 Hz), 8.12 (s, 1H), 7.91 (d, 3H, J=8.4 Hz), 7.37 (m, 4H), 7.28 (s,2H), 3.73 (br s, 4H), 2.65 (br s, 4H); LCMS (m/z): 489 (MH⁺).

IX-35:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-thiomorpholinyl)carbonylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.53 (s, 1H), 9.48 (s, 1H), 8.13 (t, 2H,J=2.1 Hz), 7.92 (d, 2H, J=8.4 Hz), 7.87 (dd, 1H, J=2.4 and 8.2 Hz), 7.35(d, 2H, J=8.7 Hz), 7.25 (s, 2H), 7.20 (d, 1H, J=8.1 Hz), 3.73 (br s,4H), 2.65 (br s, 4H), 2.46 (s, 3H); LCMS (m/z): 489 (MH⁺).

IX-23:N4-[4-(1-Acetyl-4-piperizinyl)carbonylphenyl]-N2-(3-Aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.58 (s, 2H), 8.17 (d, 1H, J=3.6 Hz), 8.13(s, 1H), 7.91 (m, 3H), 7.38 (m, 5H), 7.25 (br s, 1H), 3.72 (br s, 4H),2.48 (br s, 8H), 2.02 (s, 3H); LCMS (m/z): 514 (MH⁺).

IX-24:N4-[4-(1-Acetyl-4-piperizinyl)carbonylphenyl]-N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.54 (s, 1H), 9.48 (s, 1H), 8.14 (d, 2H,J=3.0 Hz), 7.93 (d, 2H, J=8.1 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.38 (d, 2H,J=7.8 Hz), 7.25 (s, 2H), 7.19 (d, 1H, J=8.4 Hz), 3.49 (br s, 8H), 2.50(s, 3H), 2.05 (s, 3H); LCMS (m/z): 528 (MH⁺).

IX-25:N4-[4-(1-Acetyl-4-piperizinyl)carbonylphenyl]-5-fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.55 (s, 1H), 9.48 (s, 1H), 8.15 (d, 1H,J=3.3 Hz), 8.05 (s, 1H), 7.92 (d, 3H, J=8.1 Hz), 7.38 (d, 2H, J=8.4 Hz),7.35 (q, 1H, J=5.4 Hz), 7.23 (d, 1H, J=8.1 Hz), 3.49 (br s, 8H), 2.47(s, 3H), 2.41 (d, 3H, J=4.8 Hz), 2.02 (s, 3H); LCMS (m/z): 542 (MH⁺).

IX-29:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-methanesulfonyl-4-piperizinyl)carbonylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.60 (s, 2H), 8.18 (d, 1H, J=3.6 Hz), 8.15(s, 1H), 7.93 (m, 3H), 7.38 (m, 4H), 7.28 (s, 2H), 3.60 (br s, 4H), 3.17(br s, 4H), 2.90 (s, 3H), 2.91 (s, 3H); LCMS (m/z): 550 (MH⁺).

IX-30:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1-methanesulfonyl-4-piperizinyl)carbonylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.55 (s, 1H), 9.48 (s, 1H), 8.13 (m, 2H),7.94 (d, 2H, J=9.0 Hz), 7.85 (dd, 1H, J=2.4 and 8.5 Hz), 7.38 (d, 1H,J=8.7 Hz), 7.24 (s, 2H), 7.20 (d, 1H, J=8.4 Hz), 3.61 (br s, 4H), 3.17(br s, 4H), 2.90 (s, 3H), 2.50 (s, 3H); LCMS (m/z): 564 (MH⁺).

IX-31:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(1-methanesulfonyl-4-piperizinyl)carbonylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.56 (s, 1H), 9.49 (s, 1H), 8.16 (d, 1H,J=3.3 Hz), 8.05 (d, 1H, J=2.1 Hz), 7.92 (m, 1H), 7.39 (d, 2H, J=8.4 Hz),7.34 (q, 1H, J=5.1 Hz), 7.23 (d, 1H, J=8.1 Hz), 3.61 (br s, 4H), 3.17(br s, 4H), 2.90 (s, 3H), 2.41 (d, 3H, J=4.2 Hz); LCMS (m/z): 578 (MH⁺).

III-83:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.41 (s, 2H), 8.09 (d, 1H, J=3.3 Hz), 8.00(d, 1H, J=2.1 Hz), 7.92 (dd, 1H, J=2.4 and 8.5 Hz), 7.75 (d, 3H, J=8.1Hz), 7.32 (q, 1H, J=4.5 Hz), 7.22 (d, 3H, J=8.7 Hz), 7.13 (d, 1H, J=8.4Hz), 6.94 (br s, 1H), 5.15 (s, 2H), 2.46 (s, 3H), 2.41 (d, 3H, J=4.5Hz); LCMS (m/z): 468 (MH⁺).

IX-37:N2-(3-Aminosulfonylphenyl)-N4-[4-(1,1-dioxo-4-thiomorpholinyl)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.61 (s, 1H), 9.59 (s, 1H), 8.18 (d, 1H,J=3.3 Hz), 8.13 (s, 1H), 7.92 (d, 3H, J=8.7 Hz), 7.45 (d, 2H, J=8.4 Hz),7.39 (m, 2H), 7.28 (s, 2H), 3.89 (br s, 4H), 3.26 (br s, 4H); LCMS(m/z): 521 (MH⁺).

IX-38:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(1,1-dioxo-4-thiomorpholinyl)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.54 (s, 1H), 9.48 (s, 1H), 8.14 (m, 2H),7.94 (d, 2H, J=8.1 Hz), 7.85 (d, 1H, J=8.5 Hz), 7.44 (d, 2H, J=7.8 Hz),7.24 (s, 2H), 7.20 (d, 1H, J=8.1 Hz), 3.88 (br s, 4H), 3.25 (br s, 4H),2.50 (s, 3H); LCMS (m/z): 535 (MH⁺).

IX-39:N4-[4-(1,1-dioxo-4-thiomorpholinyl)carbonylphenyl]-5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.55 (s, 1H), 9.49 (s, 1H), 8.15 (d, 1H,J=3.9 Hz), 8.05 (d, 1H, J=2.1 Hz), 7.93 (m, 3H), 7.75 (d, 3H, J=8.1 Hz),7.44 (d, 2H, J=8.4 Hz), 7.34 (q, 1H, J=5.2 Hz), 7.24 (d, 1H, J=8.1 Hz),3.88 (br s, 4H), 3.26 (br s, 4H), 2.47 (s, 3H), 2.41 (d, 3H, J=4.5 Hz);LCMS (m/z): 549 (MH⁺).

II-16:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-pyridyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.56 (s, 1H), 9.48 (s, 1H), 8.14 (d, 2H,J=2.4 Hz), 8.00 (d, 2H, J=8.7 Hz), 7.93 (d, 2H, J=8.1 Hz), 7.83 (d, 1H,J=8.1 Hz), 7.46 (d, 2H, J=8.7 Hz), 7.23 (d, 3H, J=7.2 Hz), 6.22 (d, 2H,J=7.5 Hz), 2.48 (s, 3H); LCMS (m/z): 467 (MH⁺).

II-17:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.59 (s, 2H), 8.17 (d, 1H, J=3.3 Hz), 8.13(s, 1H), 7.99 (d, 2H, J=8.7 Hz), 7.94 (d, 2H, J=7.8 Hz), 7.88 (d, 1H,J=8.1 Hz), 7.45 (m, 2H), 7.37 (m, 1H), 7.27 (s, 2H), 6.22 (d, 2H, J=7.5Hz)); LCMS (m/z): 453 (MH⁺).

II-18:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-5-fluoro-N4-[4-(4-pyridyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.58 (s, 1H), 9.49 (s, 1H), 8.15 (d, 1H,J=3.9 Hz), 8.05-7.88 (m, 6H), 7.46 (d, 2H, J=8.7 Hz), 7.34 (q, 1H, J=5.1Hz), 7.26 (d, 1H, J=8.7 Hz), 6.22 (d, 2H, J=7.8 Hz), 2.47 (s, 3H), 2.41(d, 3H, J=4.8 Hz); LCMS (m/z): 481 (MH⁺).

IX-36:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-thiomorpholinyl)carbonylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.68 (s, 1H), 9.61 (s, 1H), 8.20 (d, 1H,J=3.6 Hz), 7.86 (d, 2H, J=8.7 Hz), 7.81 (d, 2H, J=9.0 Hz), 7.63 (d, 2H,J=8.7 Hz), 7.37 (d, 2H, J=8.1 Hz), 7.12 (s, 2H), 3.74 (br s, 4H), 2.65(br s, 4H); LCMS (m/z): 489 (MH⁺).

IX-32:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-methanesulfonyl-4-piperazinyl)carbonylphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.69 (s, 1H), 9.64 (s, 1H), 8.20 (d, 1H,J=3.6 Hz), 7.90 (d, 2H, J=8.7 Hz), 7.82 (d, 2H, J=9.0 Hz), 7.65 (d, 2H,J=9.0 Hz), 7.41 (d, 2H, J=8.4 Hz), 7.13 (s, 2H), 3.61 (br s, 4H), 3.17(br s, 4H), 2.91 (s, 3H); LCMS (m/z): 550 (MH⁺).

IX-40:N2-(4-Aminosulfonylphenyl)-N4-[4-(1,1-dioxo-4-thiomorpholinyl)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.67 (s, 1H), 9.66 (s, 1H), 8.18 (d, 1H,J=3.5 Hz), 7.92 (d, 2H, J=9.0 Hz), 7.80 (d, 2H, J=8.2 Hz), 7.66 (d, 2H,J=8.7 Hz), 7.43 (d, 2H, J=9.0 Hz), 7.13 (s, 2H), 3.63 (br s, 4H), 3.15(br s, 4H); LCMS (m/z): 521 (MH⁺).

IX-26:N4-[4-(1-Acetyl-4-piperizinyl)carbonylphenyl]-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.69 (s, 1H), 9.65 (s, 1H), 8.19 (d, 1H,J=3.6 Hz), 7.87 (d, 2H, J=8.1 Hz), 7.82 (d, 2H, J=9.0 Hz), 7.63 (d, 2H,J=8.7 Hz), 7.41 (d, 2H, J=8.4 Hz), 7.13 (s, 2H), 3.49 (br s, 8H), 2.02(s, 3H); LCMS (m/z): 514 (MH⁺).

I-167:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[(4-((pyridin-2-yl)methoxy)-3-methylphenyl)]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.44 (s, 1H), 9.19 (s, 1H), 8.56 (d, 1H,J=3.9 Hz), 8.05 (d, 1H, J=3.6 Hz), 8.02 (s, 1H), 7.98 (m, 1H), 7.84 (t,1H, J=7.5 Hz), 7.51 (m, 3H), 7.30 (m, 5H), 6.92 (d, 2H, J=7.8 Hz), 5.19(s, 2H), 2.25 (s, 3H); LCMS (m/z): 481 (MH⁺).

I-168:N2-(3-Amino-4-methylsulfonylphenyl)-5-fluoro-N4-[(4-((pyridin-2-yl)methoxy)-3-methylphenyl)]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.33 (s, 1H), 9.15 (s, 1H), 8.57 (d, 1H,J=4.5 Hz), 8.05 (s, 1H), 8.02 (d, 1H, J=3.6 Hz), 7.89 (m, 1H), 7.82 (d,1H, J=7.5 Hz), 7.52 (m, 3H), 7.33 (m, 1H), 7.22 (s, 2H), 7.11 (d, 1H,J=8.1 Hz), 6.93 (d, 1H, J=9.6 Hz), 5.19 (s, 2H), 2.49 (s, 3H), 2.25 (s,3H); LCMS (m/z): 495 (MH⁺).

III-73:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridylmethyl)phenyl]-2,4-pyrimidinediamineHydrochloride Salt

N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridylmethyl)phenyl]-2,4-pyrimidinediamineIII-70, 50 mg) was dissolved in methanol (10 mL), 4N HCl (in dioxane,63.5 μL) was added and stirred the reaction mixture at room temperaturefor 1 h and concentrated under reduced pressure. Finally washed thesolid with hexanes and dried well under high vacuum resulted HCl salt inquantitative yield. ¹H NMR (DMSO d₆, 300 MHz): δ 9.92 (s, 1H), 9.82 (s,1H), 8.81 (d, 2H, J=5.4 Hz), 8.20 (d, 1H, J=4.5 Hz), 7.98 (s, 1H), 7.93(d, 1H, J=5.4 Hz), 7.87 (d, 2H, J=7.8 Hz), 7.72 (d, 2H, J=8.7 Hz),7.42-7.28 (m, 5H), 4.26 (s, 2H); LCMS (m/z): 451 (MH⁺).

The following three compounds were made in a similar fashion asdescribed above.

III-129:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridylmethyl)phenyl]-2,4-pyrimidinediamineMethanesulfonic Acid Salt

¹H NMR (DMSO d₆, 300 MHz): δ 9.61 (s, 1H), 9.55 (s, 1H), 8.79 (d, 2H,J=6.0 Hz), 8.15 (s, 1H), 8.04 (s, 1H), 7.90 (br s, 3H), 7.76 (d, 2H,J=7.5 Hz), 7.36-7.26 (m, 6H), 4.23 (s, 2H), 2.31 (s, 3H); LCMS (m/z):451 (MH⁺).

III-128:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridylmethyl)phenyl]-2,4-pyrimidinediaminep-Toluenesulfonic Acid Salt

¹H NMR (DMSO d₆, 300 MHz): δ 9.55 (s, 1H), 9.47 (s, 1H), 8.77 (d, 2H,J=5.7 Hz), 8.13 (d, 1H, J=3.6 Hz), 8.06 (s, 1H), 7.88 (m, 3H), 7.77 (d,2H, J=8.7 Hz), 7.45 (d, 2H, J=7.8 Hz), 7.34 (d, 2H, J=5.7 Hz), 7.25 (m,3H), 7.08 (d, 2H, J=8.1 Hz), 4.22 (s, 2H), 2.27 (s, 3H); LCMS (m/z): 451(MH⁺).

I-196:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-4-[(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamineHydrochloride Salt

¹H NMR (DMSO d₆, 300 MHz): δ 9.98 (s, 1H), 9.88 (s, 1H), 8.69 (d, 1H,J=4.8 Hz), 8.18 (d, 1H, J=3.9 Hz), 8.10 (t, 1H, J=8.4 Hz), 7.92 (s, 1H),7.85 (d, 1H, J=7.8 Hz), 7.73 (d, 1H, J=7.8 Hz), 7.61 (m, 3H), 7.38 (m,4H), 7.03 (d, 2H, J=9.0 Hz), 5.29 (s, 2H); LCMS (m/z): 467 (MH⁺).

III-80: Preparation ofN2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-oxido-4-pyridylmethyl)phenyl]-2,4-pyrimidinediamine

A mixture ofN2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridylmethyl)phenyl]-2,4-pyrimidinediamine(50 mg) and methyltrioxorhenium (VII) (5 mg) in THF (15 mL) was treatedwith 30% aq. H₂O₂ (23 μL). After 24 h stirring, 30% aq. H₂O₂ (23 μL) wasadded and stirred for 24 h. The reaction mixture was filtered throughCelite, washed the bed with methanol and concentrated. The residue waspurified by HPLC yielded 10 mg of desired product. ¹H NMR (DMSO d₆, 300MHz): δ 9.47 (s, 1H), 9.35 (s, 1H), 8.10 (m, 4H), 7.92 (m, 1H), 7.73 (d,2H, J=8.4 Hz), 7.32-7.18 (m, 8H), 3.91 (s, 2H); LCMS (m/z): 467 (MH⁺).

Example 35

A mixture ofN2-(3-aminosulfonylphenyl)-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine(I-230, 0.627 mg, 1.33 mmol), 4-bromomethyl-5-methyl-1,3-dioxolene-2-one(0.283 mg, 1.33 mmol) and anhydrous K₂CO₃ (0.202 g, 1.33 mmol) in DMF (5mL) were stirred at r. t. for 3 days. The reaction mixture was poured inwater (50 mL), filtered the solid and dried well. Purified by HPLC toprovide desired 1-247 (14 mg) and 1-248 (14 mg) products.

I-247:N2-{3-[(N-5-Methyl-1,3-dioxolene-2-one-4-yl)methylene]aminosulfonylphenyl}-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.49 (s, 1H), 9.29 (s, 1H), 8.22 (s, 1H),8.08 (d, 2H, J=3.9 Hz), 7.93 (m, 1H), 7.69 (d, 2H, J=9.3 Hz), 7.33 (t,1H, J=7.8 Hz), 7.24 (d, 1H, J=8.4 Hz), 6.98 (d, 2H, J=9.0 Hz), 6.32 (s,1H), 5.12 (s, 2H), 3.87 (d, 2H, J=5.1 Hz), 2.40 (s, 3H), 1.94 (s, 3H);LCMS (m/z): 583 (MH⁺).

I-248:N2-{3-[N—N-Di-[(5-Methyl-1,3-dioxolene-2-one-4-yl)methylene]]aminosulfonylphenyl}-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.48 (s, 1H), 9.32 (s, 1H), 8.19 (s, 1H),8.12 (s, 1H), 8.08 (d, 1H, J=3.3 Hz), 8.03 (d, 1H, J=9.6 Hz), 7.81 (d,2H, J=9.0 Hz), 7.39 (t, 1H, J=8.1 Hz), 7.29 (d, 1H, J=7.8 Hz), 6.99 (d,2H, J=9.0 Hz), 6.32 (s, 1H), 5.73 (s, 1H), 5.12 (s, 2H), 4.25 (s, 3H),2.40 (s, 3H), 2.04 (s, 5H); LCMS (m/z): 695 (MH⁺).

The following compounds were made in a similar fashion to the example 35or by methods described herein or known to skilled artisans.

I-249:N2-{3-[N—N-Di-[(5-t-Butyl-1,3-dioxolene-2-one-4-yl)methylene]]aminosulfonylphenyl}-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.48 (s, 1H), 9.31 (s, 1H), 8.20 (s, 1H),8.12 (s, 1H), 8.07 (d, 1H, J=3.9 Hz), 7.93 (d, 1H, J=8.7 Hz), 7.66 (d,2H, J=9.0 Hz), 7.36 (t, 1H, J=7.8 Hz), 7.21 (d, 1H, J=7.8 Hz), 6.98 (d,2H, J=8.7 Hz), 6.32 (s, 1H), 5.12 (s, 2H), 4.39 (s, 4H), 2.40 (s, 3H),1.20 (s, 18H); LCMS (m/z): 779 (MH⁺).

I-250:N2-{3-[(N-5-t-Butyl-1,3-dioxolene-2-one-4-yl)methylene]aminosulfonylphenyl}-5-fluoro-N4-[4-(5-methylisoxazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.47 (s, 1H), 9.28 (s, 1H), 8.29 (t, 1H,J=6.0 Hz), 8.12 (s, 1H), 8.07 (d, 1H, J=3.9 Hz), 7.92 (m, 1H), 7.68 (d,2H, J=9.0 Hz), 7.34 (t, 1H, J=7.8 Hz), 7.25 (d, 1H, J=8.1 Hz), 6.98 (d,2H, J=9.0 Hz), 6.32 (s, 1H), 5.12 (s, 2H), 3.93 (d, 2H, J=6.0 Hz), 2.40(s, 3H), 1.11 (s, 9H); LCMS (m/z): 625 (MH⁺).

I-257:N2-{3-[(N-5-Methyl-1,3-dioxolene-2-one-4-yl)methylene]aminosulfonylphenyl}--5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.49 (s, 1H), 9.32 (s, 1H), 8.38 (s, 1H),8.22 (s, 1H), 8.08 (d, 2H, J=2.1 Hz), 7.94 (d, 1H, J=7.8 Hz), 7.70 (d,2H, J=8.1 Hz), 7.35 (t, 1H, J=7.8 Hz), 7.25 (m, 1H), 7.01 (d, 2H, J=8.4Hz), 5.46 (s, 2H), 3.87 (s, 2H), 2.36 (s, 3H), 1.94 (s, 3H); LCMS (m/z):584 (MH⁺).

III-17:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-cyanoethyl)-3-fluorophenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.51 (s, 2H), 8.11 (s, 2H), 7.92-7.89 (d, J=8.4 Hz,1H), 7.87-7.82 (d, J=12.9 Hz, 1H), 7.60-7.58 (d, J=8.4 Hz, 1H),7.32-7.19 (m, 4H), 7.09 (s, 1H), 3.29 (s, 3H), 2.88-2.86 (bd, J=6 Hz,2H), 2.82-2.80 (bd, J=5.7 Hz, 2H), LCMS: 445.01 (MH⁺).

III-18:N2-(3-Aminosulfonylphenyl)-N4-[4-(2-cyanoethyl)-3-fluorophenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.62 (s, 1H), 9.55 (s, 1H), 8.16-8.15 (d, J=3.9 Hz,1H) 8.10 (s, 1H), 7.98-7.96 (d, J=6.9 Hz, 1H), 7.87-7.83 (dd, J=12.9 Hz,1H), 7.61-7.58 (dd, J=8.4 Hz, 1H), 7.43-7.23 (m, 5H), 2.93-2.77 (m, 4H),LCMS: 430.98 (MH⁺).

III-19:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(2-cyanoethyl)-3-methylphenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.39 (s, 1H), 9.24 (s, 1H), 8.06-8.05 (d, J=3.9 Hz,1H), 7.95-7.91 (dd, J=8.7 Hz, 1H), 7.63-7.59 (dd, J=8.1 Hz, 1H), 7.55(s, 1H), 7.21 (s, 2H), 7.14 (s, 1H), 2.86-2.83 (t, 2H), 2.79-2.74 (t,2H), LCMS: 441.49 (MH⁺).

III-20:N2-(3-Aminosulfonylphenyl)-N4-[4-(2-cyanoethyl)-3-methylphenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.50 (s, 1H), 9.28 (s, 1H), 8.10 (bs, 1H), 8.04 (bs,1H), 7.60 (d, 1H), 7.55 (s, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 6.98 (s,2H), 2.86 (m, 2H), 2.79 (s, 2H), 2.29 (s, 3H), LCMS: 427.45 (MH⁺).

III-21:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-chloro-4-(2-cyanoethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.49 (s, 1H), 9.47 (s, 1H), 8.13-8.12 (d, J=3.6 Hz,1H), 8.06-8.06 (d, J=2.1 Hz, 1H), 7.92-7.90 (dd, J=8.4 Hz, 1H),7.88-7.88 (d, J=2.1 Hz, 1H), 7.85-7.82 (dd, J=8.4 Hz, 1H), 7.37-7.34 (d,J=8.4 Hz, 1H), 7.23 (s, 2H), 7.19 (s, 1H), 3.00-2.95 (t, 2H), 3.84-2.80(t, 2H), 2.48 (s, 3H), LCMS: 460.94 (MH⁺).

III-22:N2-(3-Aminosulfonylphenyl)-N4-[3-chloro-4-(2-cyanoethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.60 (s, 1H), 9.50 (s, 1H), 8.16-8.15 (d, J=3.3 Hz,1H), 8.05, (s, 1H), 8.00-7.97 (d, J=9 Hz, 1H), 7.89-7.88 (d, J=2.1 Hz,1H), 7.85-7.82 (d, J=8.1 Hz, 1H), 7.44-7.38 (t, 1H), 7.37 (s, 1H), 7.34(s, 2H), 7.32 (s, 1H), 3.00-2.95 (t, 2H), 2.84-2.79 (t, 2H), LCMS:446.93 (MH⁺).

VII-1:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[(2S,4R)-1-(2-cyanoacetyl)-2-methoxycarbonylpyrrolidin-4-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.34 (s, 1H), 8.41-8.40 (d, J=2.1 Hz, 1H), 7.92-7.90(d, J=3.9 Hz, 1H), 7.76-7.73 (d, J=6.3 Hz, 1H), 7.67-7.63 (dd, J=7.8 Hz,1H), 7.20 (s, 2H), 7.17 (s, 1H), 4.73 (bs, 1H), 4.53-4.47 (t, 1H), 4.03(bs, 2H), 3.91-3.85 (m, 1H), 3.65 (s, 1H), 3.55-3.51 (d, J=10.8 Hz, 1H),2.43-2.36 (m, 1H), 2.20-2.15 (m, 1H), LCMS: 492.20 (MH⁺).

VII-2:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[(2S,4S)-1-(2-cyanoacetyl)-2-methoxycarbonylpyrrolidin-4-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.37 (s, 1H), 8.69 (s, 1H), 7.93-7.92 (d, J=3.3 Hz,1H), 7.59-7.56 (d, J=7.5 Hz, 1H), 7.46-7.43 (dd, J=8.4 Hz, 1H), 7.19 (s,1H), 7.17 (s, 2H), 4.84-4.82 (m, 1H), 4.39-4.33 (t, 1H), 3.94-3.89 (t,1H), 3.64 (s, 3H), 3.44-3.38 (t, 1H), 2.63-2.59 (m, 1H), 2.07-2.00 (m,1H), LCMS: 492.79 (MH⁺).

VII-77:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-8-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.71 (s, 1H), 9.66 (s, 1H), 9.00-8.98 (d, J=7.2 Hz,1H), 8.94-8.93 (d, J=3.6 Hz, 1H), 8.45-8.42 (d, J=8.1 Hz, 1H), 8.25-8.24(d, J=3.0 Hz, 1H), 8.21-8.21 (d, J=2.1 Hz, 1H), 7.91-7.87 dd, J=7.8 Hz,1H), 7.68-7.67 (d, J=3.9 Hz, 1H), 7.66 (s, 2H), 7.28 (s, 2H), 2.53 (s,3H), LCMS: 425.68 (MH⁺).

VII-78:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(quinolin-8-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.78 (s, 1H), 9.74-9.74 (d, J=2.7 Hz, 1H), 9.00-8.97(dd, J=6.9 Hz, 1H), 8.95-8.93 (dd, J=3.9 Hz, 1H), 8.46-8.42 (dd, J=8.4Hz, 1H), 8.28-8.27 (d, J=3.3 Hz, 1H), 8.23 (s, 1H), 7.93-7.91 (d, J=8.1Hz, 1H), 7.68-7.63 (m, 3H), 7.49-7.38 (m, 2H), 7.303 (s, 1H), LCMS:411.60 (MH+).

VII-79:N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(quinolin-8-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.73 (s, 2H), 8.96 (s, 1H), 8.94-8.94 (d, J=2.4 Hz,1H), 8.45-8.43 (d, J=6.9 Hz, 1H), 8.26-8.25 (d, J=3.0 Hz, 1H), 8.19-8.16(dd, J=6 Hz, 1H), 7.99-7.94 (m, 1H), 7.68-7.63 (m, 3H), 7.59 (s, 2H),7.37-7.31 (t, 1H), LCMS: 429.40 (MH⁺).

VII-69:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.69 (s, 1H), 9.48 (s, 1H), 8.76-8.74 (dd, J=4.2 Hz,1H), 8.61-8.61 (d, J=2.1 Hz, 1H), 8.21-8.19 (d, J=7.2 Hz, 1H), 8.16-8.15(d, J=3.6 Hz, 1H), 8.12-8.11 (d, J=2.4 Hz, 1H), 8.10-8.06 (dd, J=9.0 Hz,1H), 7.95-7.92 (d, J=9.3 Hz, 1H), 7.94-7.91 (d, J=8.4 Hz, 1H), 7.50-7.46(m, 1H), 7.25 (s, 2H), 7.17-7.14 (d, J=8.4 Hz, 1H), LCMS: 425 (MH⁺).

VII-70:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(quinolin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.96 (s, 1H), 9.68 (s, 1H), 8.95-8.94 (d, J=4.2 Hz,1H), 8.82 (s, 1H), 8.61-8.59 (d, J=7.5 Hz, 1H), 8.28-8.24 (m, 2H),8.12-8.07 (m, 2H), 7.99-7.96 (m, 1H), 7.78-7.75 (m, 1H), 7.40-7.38 (m,2H), 7.28 (s, 2H), LCMS: 411.11 (MH⁺).

VII-57:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(benzothiophen-5-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.44 (s, 1H), 9.40 (s, 1H), 8.41-8.40 (s, 1H), 8.09(s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.76-7.74 (d, J=5.4Hz, 1H), 7.72-7.68 (d, J=6.6 Hz, 1H), 7.37-7.35 (d, J=5.4 Hz, 1H), 7.23(s, 2H), 7.13-7.10 (d, J=8.4 Hz, 1H), LCMS: 430.37 (MH⁺).

VII-58:N2-(3-Aminosulfonylphenyl)-N4-(benzothiophen-5-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.51 (s, 1H), 9.48 (s, 1H), 8.40 (s, 1H), 8.13-8.12(d, J=3.6 Hz, 1H), 8.06 (s, 1H), 7.94 (m, 1H), 7.94-7.91 (d, J=9 Hz,1H), 7.76-7.74 (d, J=5.7 Hz, 1H), 7.72-7.68 (dd, J=2.4 Hz, 1H),7.38-7.36 (d, J=5.7 Hz, 1H), 7.33-7.32 (m, 2H), 7.25 (s, 2H), LCMS:416.39 (MH⁺).

VII-71:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(2-methylquinolin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.62 (s, 1H), 9.47 (s, 1H), 8.55 (s, 1H), 8.15-8.13(d, J=3.6 Hz, 1H), 8.10 (s, 2H), 8.05-8.01 (dd, J=9.3 Hz, 1H), 7.95-7.91(dd, J=8.1 Hz, 1H), 7.85-7.82 (d, J=9.3 Hz, 1H), 7.38-7.36 (d, J=8.4 Hz,1H), 7.25 (s, 2H), 7.17-7.14 (d, J=8.4 Hz, 1H), 2.62 (s, 3H), 2.51 (s,3H), LCMS: 439.41 (MH⁺).

VII-72:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(2-methylquinolin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.55 (s, 1H), 8.55 (s, 1H), 8.16-8.16 (d, J=3.3 Hz,1H), 8.13 (s, 1H), 8.10-8.08 (d, J=4.5 Hz, 1H), 8.04 (bs, 1H), 8.01 (bs,1H), 7.85-7.82 (d, J=8.7 Hz, 1H), 7.38-7.33 (m, 3H), 2.62 (s, 3H), LCMS:425.57 (MH⁺).

VII-65:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-3-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.47 (s, 1H), 9.19 (s, 1H), 8.86 (s, 1H), 8.15-8.12(m, 2H), 7.92-7.84 (m, 4H), 7.61-7.52 (m, 2H), 7.17-7.14 (d, J=8.1 Hz,1H), 2.42 (s, 3H), LCMS: 425.79 (MH⁺).

VII-66:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(quinolin-3-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.46 (s, 1H), 9.14 (s, 1H), 8.80 (s, 1H), 8.12-8.08(m, 2H), 7.95-7.84 (m, 4H), 7.59-7.53 (m, 3H), 7.34-7.32 (m, 3H), LCMS:411.44 (MH⁺).

VII-67:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-5-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.15 (s, 1H), 8.89-8.87 (d, J=3.3 Hz, 1H), 8.34-8.31(d, J=8.4 Hz, 1H), 8.08-8.07 (d, J=3.6 Hz, 1H), 7.96-7.93 (d, J=8.7 Hz,1H), 7.88 (s, 1H), 7.81-7.75 (t, 1H), 7.66-7.64 (d, J=6.9 Hz, 1H),7.50-7.46 (m, 2H), 7.36 (s, 1H), 7.34 (s, 1H), 6.70-6.68 (d, J=8.1 Hz,1H), 2.38 (s, 3H), LCMS: 425.71 (MH⁺).

VII-68:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(quinolin-5-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.15 (s, 1H), 8.85 (s, 1H), 8.40-8.38 (d, J=7.8 Hz,1H), 8.00 (s, 1H), 7.87-7.83 (m, 2H), 7.77-7.67 (m, 2H), 7.53-7.50 (d,J=7.8 Hz, 1H), 7.47-7.42 (m, 2H), 7.17-7.14 (d, J=7.5 Hz, 1H), 6.95-6.90(t, 1H), LCMS: 411.58 (MH⁺).

VII-80:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(2-methylquinolin-8-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.81 (s, 1H), 9.71 (s, 1H), 8.91 (s, 1H), 8.34-8.31(d, J=8.4 Hz, 1H), 8.24-8.23 (d, J=3.3 Hz, 1H), 8.17 (s, 1H), 7.87-7.85(d, J=6.9 Hz, 1H), 7.63-7.51 (m, 3H), 7.27-7.24 (m, 3H), 2.73 (s, 3H),2.53 (s, 3H), LCMS: 439.16 (MH⁺).

VII-81:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(2-methylquinolin-8-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.84 (s, 1H), 9.81 (s, 1H), 8.87 (s, 1H), 8.35-8.33(d, J=8.4 Hz, 1H), 8.28-8.27 (d, J=3.3 Hz, 1H), 8.18 (s, 1H), 7.90-7.88(m, 1H), 7.65-7.62 (m, 1H), 7.58-7.53 (m, 2H), 7.45-7.39 (m, 2H), 7.30(s, 2H), 2.74 (s, 3H), LCMS: 425.06 (MH⁺).

VII-64:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(quinolin-2-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.59 (s, 1H), 8.31 (s, 1H), 8.22-8.21 (d, J=3.3 Hz,1H), 8.10 (s, 1H), 8.00-7.97 (dd, J=8.1 Hz, 1H), 7.96-7.89 (d, J=8.1 Hz,1H), 7.81-7.78 (d, J=8.1 Hz, 1H), 7.71-7.65 (t, 1H), 7.48-7.43 (t, 1H),7.25 (s, 2H), 7.19-7.16 (d, J=8.4 Hz, 1H), 7.09 (s, 1H), 2.54 (s, 3H),LCMS: 425.87 (MH⁺).

III-13:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-[4-(2-cyanoethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.52 (s, 1H), 8.25-8.24 (d, J=2.7 Hz, 1H),8.10-8.09 (d, J=3.9 Hz, 1H), 8.03-7.99 (dd, J=8.7 Hz, 1H), 7.75-7.73 (d,J=8.4 Hz, 2H), 7.40-7.37 (d, J=8.7 Hz, 1H), 7.26-7.23 (d, J=8.4 Hz, 2H),2.85-2.78 (m, 4H), LCMS: 447.45 (MH⁺).

III-11:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanoethylenephenyl)-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.17 (s, 1H), 8.22 (s, 1H), 8.07-8.07 (d, J=2.1 Hz,1H), 7.96-7.92 (dd, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.69-7.66 (d, J=8.4 Hz,2H), 7.23-7.20 (d, J=8.7 Hz, 2H), 7.16-7.11 (m, 2H), 2.85-2.80 (m, 4H),2.10 (s, 3H), LCMS: 424.01 (MH⁺).

III-12:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-[4-(2-cyanoethyl)phenyl]-5-methyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.45 (s, 1H), 9.41 (s, 1H), 8.30-8.25 (m, 2H),8.09-8.05 (d, J=8.7 Hz, 1H), 7.88 (s, 1H), 7.67-7.64 (d, J=8.4 Hz, 2H),7.42 (s, 2H), 7.37-7.34 (d, J=8.7 Hz, 2H), 7.25-7.22 (d, J=8.4 Hz, 2H),2.88-2.79 (m, 4H), 2.11 (s, 3H), LCMS: 443.51 (MH+).

VI-103:N4-[4(2-Cyanoethyl)-3-methylphenyl]-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.40 (s, 1H), 9.23 (s, 1H), 8.10-8.03 (m, 2H),8.00-7.69 (d, J=8.4 Hz, 1H), 7.62-7.59 (d, J=8.1 Hz, 1H), 7.56 (s, 1H),7.17-7.12 (t, 2H), 6.66-6.64 (d, J=5.1 Hz, 2H), 2.85-2.83 (m, 2H),2.78-2.75 (m, 2H), 2.45 (s, 3H), 2.27 (s, 3H), 2.16-2.11 (q, 2H),0.90-0.85 (t, 3H), LCMS: 497.50 (MH⁺).

VI-104:N4-[4-(2-Cyanoethyl)-3-methylphenyl]-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamineSodium Salt

¹H NMR (DMSO-d₆): δ 9.18 (s, 1H), 9.15 (s, 1H), 8.03-8.02 (d, J=3.6 Hz,1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.64-7.62 (d. J=8.1 Hz, 1H), 7.60 (s,1H), 7.16-7.13 (d, J=8.4 Hz, 1H), 6.96-6.93 (d, J=7.8 Hz, 1H), 2.85-2.83(m, 2H), 2.78-2.76 (m, 2H), 2.41 (s, 1H), 2.28 (s, 1H), 1.94-1.87 (q,2H), 0.87-0.82 (t, 3H), LCMS: 497.44 (MH⁺).

V11-39:5-Amino-N2-(3-amionsulfonylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.55 (s, 1H), 8.86 (s, 1H), 8.21 (s, 1H), 8.07 (s,1H), 7.95 (d, 1H, J=8.0 Hz), 7.61 (d, 1H, J=1.3 Hz), 7.39 (dd, 1H, J=1.3and 8.8 Hz), 7.30-7.21 (m, 5H), 6.87 (d, 1H, J=8.8 Hz), 1.39 (s, 6H).LCMS: ret. time: 3.51 min.; purity: 99%; MS (m/e): 456 (MH⁺).

VII-22:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(3-methoxypropyl)indazolin-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.48 (s, 1H), 9.41 (s, 1H), 8.20 (s, 1H), 8.10 (d,1H, J=3.8 Hz), 8.05 (s, 1H), 7.99 (s, 1H), 7.99-7.96 (m, 1H), 7.64 (d,1H, J=9.1 Hz), 7.58 (d, 1H, J=9.1 Hz), 7.31-7.25 (app m, 4H), 4.42 (t,2H, J=6.7 Hz), 3.32 (s, 3H), 3.23 (t, 2H, J=6.7 Hz), 2.04 (qt, 2H, J=6.7Hz). LCMS: ret. time: 4.59 min.; purity: 99%; MS (m/e): 472 (MH⁺).

VII-23:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(2-methoxyethyl)indazolin-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.47 (s, 1H), 9.40 (s, 1H), 8.16 (s, 1H), 8.10 (d,1H, J=3.5 Hz), 8.05 (s, 1H), 7.99-7.95 (m, 2H), 7.65 (d, 1H, J=9.8 Hz),7.60 (d, 1H, J=8.8 Hz), 7.33-7.25 (m, 4H), 4.54 (t, 2H, J=5.3 Hz), 3.75(t, 2H, J=5.3 Hz), s, 3H), 3.30 (s, 3H). LCMS: ret. time: 4.31 min.;purity: 99%; MS (m/e): 458 (MH⁺).

I-1:N2-(4-Aminosulphonylphenyl)-N4-(3-cyanomethoxy-4,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.16 (d, 1H, J=2.2 Hz), 7.77 (d, 2H, J=8.3 Hz), 7.60(d, 2H, J=8.3 Hz), 7.24 (m, 1H), 7.15 (m, 1H), 5.10 (s, 2H), 3.82 (s,3H), 3.66 (s, 3H); LCMS: purity 90%; MS (m/e): 475 (MH⁺).

I-2:N2-(3-Aminosulphonyl-4-methylphenyl)-N4-(3-cyanomethoxy-4,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.10 (m, 2H), 7.89 (dd, 1H, J=2.1 and J=5.6 Hz),7.25 (m, 1H), 7.15 (m, 2H), 5.12 (s, 2H), 3.74 (s, 3H), 3.68 (s, 3H),2.48 (s, 3H); LCMS: purity 99%; MS (m/e): 489 (MH⁺).

V-4: RacemicN2-(4-Aminosulphonylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine

Purity 90%; MS (m/e): 565 (MH⁺).

V-5: RacemicN2-(3-Aminosulphonylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine

purity 90%; MS (m/e): 565 (MH⁺).

V-6:N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.20 (d, 1H, J=3.9 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.63(d, 2H, J=8.4 Hz), 7.53 (m, 2H), 7.07 (m, 1H), 5.00 (s, 2H), 4.77 (s,2H); purity 92%; MS (m/e): 470 (MH⁺).

V-7:N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.18 (d, 1H, J=3.3 Hz), 8.05 (s, 1H), 7.82 (s, 1H,),7.54 (m, 2H), 7.38 (m, 2H), 4.99 (s, 2H), 4.76 (s, 2H); purity 90%; MS(m/e): 470 (MH⁺).

VII-11:N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(2,2,4-trimethyl-1,1,3-trioxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.28 (d, 1H, 3.3 Hz), 8.13 (s, 1H), 7.98 (m, 4H),7.89 (m, 1H), 7.80 (m, 1H), 7.77 (m, 1H), 7.40 (m, 2H), 3.34 (s, 3H),1.43 (s, 6H); purity 91%; MS (m/e): 521 (MH⁺).

VII-12:N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(2,2,4-trimethyl-1,1,3-trioxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

Purity 90%; MS (m/e): 521 (MH⁺).

V-11:N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.21 (d, 1H, J=3.2 Hz), 7.80 (m, 3H), 7.64 (m, 2H),7.42 (m, 1H), 7.13 (s, 1H), 5.00 (s, 2H), 3.66 (s, 2H); purity 93%; MS(m/e): 486 (MH⁺).

V-12:N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.18 (d, 1H, J=3.4 Hz), 8.14 (s, 1H), 7.88 (m, 1H),7.80 (m, 1H), 7.38 (m, 3H) 7.27 (s, 1H), 4.99 (s, 2H), 3.65 (s, 2H);purity 93%; MS (m/e): 486 (MH⁺).

V-8:N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[3-oxo-4-cyanomethyl-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.11 (m, 2H), 7.80 (m, 1H), 7.61 (m, 2H), 7.18 (s,1H), 7.02 (d, 1H, J=8.4 Hz), 5.00 (s, 2H), 4.75 (s, 2H), 3.54 (s, 3H);purity 95%; MS (m/e): 484 (MH⁺).

V-13:N2-(3-Aminosulphonyl4-methylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.17 (d, 1H, J=3.4 Hz), 8.11 (s, 1H), 7.64 (m, 2H),7.27 (m, 1H), 7.19 (m, 2H), 4.96 (s, 2H), 4.75 (s, 2H), 3.65 (s, 3H);purity 95%; MS (m/e): 500 (MH⁺).

VII-46:N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(2,2,4-trimethyl-1,1,3-trioxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

Purity 90%; MS (m/e): 514 (MH⁺).

VII-47:N2-(4-Aminosulphonylphenyl)-N4-cyanomethyl-5-fluoro-N4-[3-oxo-4-methyl-benzo[1,4]thiazin-6-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.21 (d, 1H, J=4.8 Hz), 7.88 (d, 2H, J=8.7 Hz), 7.69(d, 2H, J=8.7 Hz), 7.46 (d, 1H, J=7.2 Hz), 7.33 (bs, 1H), 7.04 (m, 1H),5.00 (s, 2H), 3.56 (s, 2H), 3.31 (s, 3H); purity 99%; MS (m/e): 500(MH⁺).

V-9:(R/S)—N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benzo[1,4]thiazin-6-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.10 (d, 1H, J=2.2 Hz), 7.82 (m, 1H), 7.63 (m, 2H),7.16 (m, 3H), 7.04 (d, 2H, J=8.1 Hz), 6.78 (d, 2H, J=8.1 Hz), 5.00 (m,2H), 3.76 (q, 1H, J=6.6 Hz), 3.63 (s, 3H), 3.34 (s, 3H), 1.36 (d, 3H,J=6.6 Hz); purity 90%; MS (m/e): 595 (MH⁺).

V-10:(R/S)—N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benzo[1,4]thiazin-6-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.15 (d, 1H, J=3.6 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.65(m, 2H), 7.52 (bs, 1H), 7.34 (d, 1H, J=8.4 Hz), 7.13 (s, 1H), 7.07 (d,2H, J=8.4 Hz), 6.79 (d, 2H, J=8.4 Hz), 5.06 (s, 2H), 3.79 (q, 1H, J=6.9Hz), 3.64 (s, 3H), 1.38 (d, 3H, J=6.9 Hz); purity 99%; MS (m/e): 581(MH⁺).

V-2:N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethy)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine

Purity 90%; MS (m/e): 536 (MH⁺).

V-3:N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethy)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine

Purity 90%; MS (m/e): 522 (MH⁺).

VII-36:N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

(LCMS (m/z): 445 (MH⁺).

VII-44:N2-(3-Aminosulphonyl-4-methyl-phenyl)-5-fluoro-N4-(3-oxo-4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

LCMS (m/z): 461 (MH⁺).

VII-45:N2-(3-Aminosulphonyl-4-methyl-phenyl)-5-fluoro-N4-(3-oxo-4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

LCMS (m/z): 475 (MH⁺).

I-268:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-[3-methyl-1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.58 (s, 1H), 9.37 (s, 1H), 7.79 (d, 2H, J=8.7 Hz),7.86 (d, 2H, J=8.7 Hz), 7.62 (d, 2H, J=8.7 Hz), 7.12 (s, 2H), 7.03 (d,2H, J=8.7 Hz), 5.47 (s, 2H), 2.36 (s, 3H); LCMS: purity: 100%; MS (m/e):472.4 (MH+).

I-271:N2-(5-N,N-Diethylaminosulfonyl-2-methoxyphenyl)-5-fluoro-N4-(4-[3-methyl-1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4-pyrimidinediamine

LCMS: purity: 91.7%; MS (m/e): 558.5 (MH+).

I-272:5-Fluoro-N4-(4-[3-methyl-1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-N2-(5-piperidinesulfonylphenyl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 558.5 (MH+).

VII-48:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

LCMS: purity: 96.5%; MS (m/e): 461.4 (MH+).

VII-49:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

LCMS: purity: 97.4%; MS (m/e): 461.4 (MH+).

VII-40:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine

LCMS: purity: 97.1%; MS (m/e): 445.1 (MH+).

VII-41:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine

LCMS: purity: 97.1%; MS (m/e): 445.1 (MH+).

VII-50:5-Fluoro-N4-(4-methyl-3-oxo-benz[1,4]thiazin-6-yl)-N2-(3-piperidinosulfonylphenyl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 529.4 (MH+).

VII-54:N2-(3-Aminosulfonylphenyl)-N4-(2-aminocarbonylbenzofurane-5-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 84.5%; MS (m/e): 443.4 (MH+).

IX-5:N2-(3-Aminosulfonylphenyl)-N4-(1-cyanomethyleneindol-5-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 92.6%; MS (m/e): 438.3 (MH+).

VII-59:N2-(4-Aminosulfonylphenyl)-N4-(4-N-tert-butoxycarbonylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 97.7%; MS (m/e): 473.4 (MH+).

IX-6:N2-(4-Aminosulfonylphenyl)-N4-(1-cyanomethyleneindol-5-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 438.4 (MH+).

IX-7:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(1-cyanomethyleneindol-5-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 452.4 (MH+).

IX-8:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(1-cyanomethyleneindol-5-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 472.4 (MH+).

Example 36

V-18:N-2-(3-aminosulfonyl-4-methylphenyl)-N4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine

A heterogeneous mixture ofN4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-2-chloro-5-fluoro-4-pyrimidineamine(40 mg, 0.123 mmol), 4-methyl-aminobenzene-3-sulfonamide (25.5 mg, 0.148mmol) and trifluoroacetic acid (50 μL) in MeOH (2 mL) was heated insealed reaction vial at 100° C. for 24 h. The resulting reaction mixturewas purified by silica gel column chromatography using 1-3% 2N NH₃/MeOHin CH₂Cl₂ to provide desired 20.0 mg (34%) ofN2-(3-aminosulfony-4-methylphenyl)-N4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 11.08 (s, 1H), 9.46 (s, 1H), 8.12 (d, 1H, J=3.6 Hz),8.07 (d, 1H, J=2.1 Hz), 7.88 (m, 1H), 7.64 (d, 1H, J=8.4 Hz), 7.38 (d,1H, J=10.2 Hz), 7.24 (s, 2H), 7.16 (d, 1H, J=8.1 Hz), 2.49 (s, 3H), 1.43(s, 6H): LCMS: purity: 97%; MS (m/e): 475 (MH⁺).

Example 37

VII-30:N2-(3-Aminosulphonyl-4-methylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine

A mixture of 250 mg of 6-Amino-3-oxo-4H-benz[1,4]oxazine and 460 mg of2,4-dichloro-5-methylpyrimidine in 15 mL methanol was stirred overnightat RT and solvent volume was reduced by using rotary evaporation. Thesolution was filtered and the filtrate diluted with water andneutralized with sodium bicarbonate. The precipitate was collected bysuction filtration washed with water and dried on the funnel to yield 75mg (20%) of the desired product2-chloro-5-methyl-N4-oxo-benz[1,4]oxazin-6-yl)-4-pyrimidineamine. ¹H NMR(DMSO-d6): δ 7.98 (s, 1H), 7.08 (m, 2H), 6.91 (d, 1H J=6 Hz), 4.54 (s,2H), 2.11 (s, 3H) purity 97%; MS (m/e) 291 (MH⁺).

A heterogeneous mixture of2-chloro-5-methyl-N4-oxo-benz[1,4]oxazin-6-yl)-4-pyrimidineamine (25 mg)and 3-aminosulfonyl-4-methylaniline (40 mg) in iPrOH: TFA (4:1; v/v) washeated in a sealed tube for 24 h. The resulting reaction mixture wasdiluted with water, acidified with 2N HCl and the solid obtained wasfiltered. The solid upon taking into methanol:water was neutralized byaqueous solution of sodium bicarbonate and the resulting solid wasisolated by filtration to giveN2-(3-aminosulphonyl-4-methylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine.¹H NMR (DMSO-d6): δ 7.86 (s, 1H), 7.80 (s, 1H), 7.77 (m, 1H), 7.31 (bs,2H), 7.12 (m, 2H), 6.95 (m, 1H), 4.58 (s, 2H), 2.11 (s, 3H); purity 99%;MS (m/e): 441 (MH⁺).

Example 38

III-27:N2-(4-Aminosulfonylphenyl)-N4-(4-cyanoethylenephenyl)-5-methyl-2,4-pyrimidinediamineand its prodrug

A solution of triphenylphosphine in toluene (1 mol L-1, 40 mL, 40 mmol)at 0° C. under nitrogen was added to a mixture of toluene (20 mL) andtetrahydrofuran (20 ml). Iodoacetonitrile (2.8 mL, 38.7 mmol) was thenadded drop wise with vigorous stirring. Ice-bath was removed and themixture was stirred at room temperature for an additional of 40 h. Themixture was filtered and the solid was washed with toluene andrecrystallized from acetonitrile to give 8 g of(cyanomethyl)trimethylphosphonium iodide as a white solid. LCMS: 243.03(M⁺).

Propionitrile (32 mL), diisopropylethylamine (2.5 g, 19.58 mmol) wereadded to a mixture of 4-nitrobenzyl alcohol (1 g, 6.53 mmol) and(cyanomethyl)trimethylphosphonium iodide (4 g, 16.32 mmol). The mixturewas heated at 97° C. for 24 h. Water (1 mL) was added to the mixture andfollowed by conc. HCl (5 mL). Ethyl acetate (3×100 mL) was used toextract the product. Organic layer was washed with brine, dried withsodium sulfate, concentrated to give dark brown solid. The crude productwas purified by flash column chromatography (Ethyl acetate: Hexanes 1:1)to give 740 mg of 3-(4-nitrophenyl)propionitrile as a light orangesolid. ¹H NMR (DMSO-d₆): δ 8.20-8.17 (dd, J=8.7 Hz, 2H), 7.59-7.56 (d,J=9.0 Hz, 2H), 3.06-3.01 (m, 2H).

3-(4-Nitrophenyl)propionitrile (740 mg, 4.2 mmol) was dissolved inmethanol (100 mL), 10% Pd/C was added and the mixture was shaken under ahydrogen atmosphere (50 psi) at room temperature for 30 minutes. Themixture was filtered through Celite, and washed with 20 mL of methanol.The combined organic solvent was concentrated under reduced pressure togive crude materials which was further purified by flash columnchromatography (Ethyl acetate: Hexanes 1:1) to yield 520 mg of3-(4-Aminophenyl)propionitrile as a light yellow oil. ¹H NMR (DMSO-d₆):δ 6.91-6.88 (d, J=9.0 Hz, 2H), 6.49-6.46 (d, J=9.0 Hz, 2H), 4.92 (s,2H), 2.66 (s, 4H).

3-(4-Aminophenyl)propionitrile (152 mg, 1.0 mmol) was dissolved inisopropyl alcohol (2 mL), 2,4-dichloro-5-methylpyrimidine (300 mg, 1.8mmol) was added to the solution. The mixture was stirred for 48 hours.All the solvent was removed under reduced pressure, saturated sodiumbicarbonate was added, aqueous layer was extracted with ethyl acetate.Ethyl acetate was dried with sodium sulfate, filtered, concentratedunder reduced pressure to give crude product. Crude was further purifiedby column chromatography (Ethyl Acetate:Hexanes, 1:1 to 3:1) to give 70mg of 2-Chloro-N4-(4-cyanoethylenephenyl)-5-methyl-4-pyrimidineamine asa colorless oil. ¹H NMR (DMSO-d₆): δ 8.80 (s, 1H), 8.00 (s, 1H),7.55-7.52 (d, J8.Hz, 2H), 7.271-7.244 (d, J=8.1 Hz, 2H), 2.85-2.80 (m,4H), 2.15 (s, 3H); LCMS: 275.28 (MH⁺).

2-Chloro-N4-(4-cyanoethylenephenyl)-5-methyl-4-pyrimidineamine (70 mg,0.25 mmol) was dissolved in isopropyl alcohol (2 mL). Trifluoroaceticacid (2 drops) and 4-aminosulfonylaniline (70 mg, 0.4 mmol) was added tothe solution, the mixture was heated at 100° C. for 48 hours. Solventwas removed under reduced pressure, saturated sodium bicarbonate wasadded, and extracted with ethyl acetate. Organic layer was dried withsodium sulfate, filtered and concentrated to give crude product. Thecrude product was sonicated with dichloromethane and acetonerespectively to give 120 mg ofN2-(4-Aminosulfonylphenyl)-N4-(4-cyanoethylenephenyl)-5-methyl-2,4-pyrimidinediamineas a off-white solid. ¹H NMR (DMSO-d₆): δ 8.39 (s, 1H), 8.35 (s, 1H),8.10 (s, 1H), 7.91 (s, 1H), 7.81-7.78 (d, J=8.7 Hz, 2H), 7.63-7.60 (d,J=8.4 Hz, 2H), 7.57-7.55 (d, J=8.7 Hz, 2H), 7.26-7.23 (d, J=8.4 Hz, 2H),7.07 (s, 2H), 2.88-2.81 (m, 4H), 2.11 (s, 3H); LCMS: 409.01 (MH⁺).

N2-(4-Aminosulfonylphenyl)-N4-(4-cyanoethylenephenyl)-5-methyl-2,4-pyrimidinediamine(70 mg, 0.17 mmol) was added to THF (2 mL), DMAP (10 mg, 0.5equivalent), triethylamine (0.028 mL, 1.2 equivalents), and propionicanhydride (0.024 mL, 1.1 equivalents). The mixture was shaken overnight,all the solvent was removed under reduced pressure. The residue wasextracted with dichloromethane, the organic layer was washed with water,dried, and concentrated under reduced pressure to give 20 mg of aprodrug of the compound described above,N4-(4-Cyanoethylenephenyl)-5-methyl-N2-(4-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine,as an off white solid. ¹H NMR (DMSO-d₆): δ 11.79 (s, 1H), 9.55 (s, 1H),8.39 (s, 1H), 7.92 (s, 1H), 7.84-7.81 (d, J=7.8 Hz, 2H), 7.65-7.62 (d,J=8.7 Hz, 2H), 7.61-7.59 (d, J=7.5 Hz, 2H), 7.27-7.24 (d, J=7.5 Hz, 2H),2.86-2.82 (m, 4H), 2.21-2.13 (q, 2H), 2.12 (s, 3H), 0.90-0.85 (t, 2H);LCMS: 465.02 (MH⁺).

N4-(4-Cyanoethylenephenyl)-5-methyl-N2-(4-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine(20 mg, 0.04 mmol) was dissolved in acetonitrile and water, 1N NaOH wasadded drop wise. The solution was lyophilized over 48 hours to give thesodium salt of prodrug III-27, as a light yellow solid. ¹H NMR(DMSO-d₆): δ 9.07 (s, 1H), 8.24 (s, 1H), 7.87 (s, 1H), 7.65-7.63 (d,J=6.6 Hz, 2H), 7.60-7.57 (d, J=7.2 Hz, 2H), 7.50-7.48 (d, J=7.2 Hz, 2H),7.24-7.22 (d, J=6.9 Hz, 2H), 2.87-2.81 (m, 4H), 2.10 (s, 3H), 1.89-1.86(q, 2H), 0.87-0.82 (t, 3H); LCMS: 465.02 (MH⁺).

Example 39

I-179:N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

A dry reaction flask was charged with 4-nitrophenol (3.858 g, 27.75mmol), anhydrous K₂CO₃ (8.29 g, 60 mmol) and acetone (250 mL). To thisheterogeneous mixture was added 2-pyridylmethylbromide hydrobromide (7.0g, 27.75 mmol) and refluxed for 24 h. From the resulting reactionmixture, 200 mL of acetone was removed under reduced pressure. Theresulting residue was then diluted with ice-water (1 liter), the solidcrushed out was filtered, washed with water and dried well to give2-[(4-nitrophenoxy)methyl]pyridine (6.05 g, 95% yield). ¹H NMR (CDCl₃):δ 8.61 (d, 1H, J=4.8 Hz), 8.19 (d, 2H, J=9.0 Hz), 7.72 (m, 2H), 7.46 (d,1H, J=7.8 Hz), 7.25 (m, 1H), 7.05 (d, 2H, J=9.3 Hz), 5.28 (s, 2H); LCMS(m/z): 231 (MH⁺).

2-[(4-Nitrophenoxy)methyl]pyridine (2.30 g, 10 mmol) was dissolved inethanol (160 mL) and water (40 mL). NH₄Cl (5.30 g) was added to theabove mixture and heated to 70-80° C. To this reaction mixture was addediron powder (5.50 g) in portion wise manner under a vigorous stirringand the stifling was continued for 2 h. The reaction mixture wasfiltered through a Celite pad when hot and washed the filter bed withMeOH. The filtrate was concentrated, diluted with water, extracted withCH₂Cl₂ (3×75 mL), dried and concentrated to provide2-[(4-aminophenoxy)methyl]pyridine as brown solid (1.735 g) in 86%yield. ¹H NMR (CDCl₃): δ 8.56 (m, 1H), 7.67 (m, 1H), 7.49 (d, 1H, J=7.8Hz), 7.18 (m, 1H), 6.80 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.7 Hz), 5.12(s, 2H), 3.43 (br s, 2H); LCMS (m/z): 201 (MH⁺).

A mixture of 2-[(4-aminophenoxy)methyl]pyridine (0.794 g, 3.97 mmol) and2,4-dichloro-5-methylpyridine (0.65 g, 3.97 mmol) in a mixture ofmethanol (49 mL) and water (16 mL) was stirred at room temperature for48 h. The reaction mixture was concentrated under reduced pressure toremove MeOH (30 mL) and then diluted with ice-water (200 mL). Theresulting mixture was kept aside for 1 h, the solid that separated wasfiltered, washed with water and dried to afford2-chloro-5-methyl-N-[4-(2-pyridinyl)methyleneoxyphenyl]-4-pyrimidineamine(1.21 g, 93% yield). ¹H NMR (DMSO-d₆): δ 8.60 (s, 1H), 8.56 (d, 1H,J=4.8 Hz), 7.94 (d, 1H, J=0.9 Hz), 7.81 (m, 1H), 7.52 (s, 1H), 7.48 (d,2H, J=9.3 Hz), 7.31 (dd, 1H, J=4.8 and 7.5 Hz), 7.02 (d, 2H, J=9.0 Hz),5.17 (s, 2H), 2.14 (s, 3H); LCMS (m/z): 327 (MH⁺).

2-Chloro-5-methyl-N-[4-(2-pyridinyl)methyleneoxyphenyl]-4-pyrimidineamine(1.21 g) was dissolved in MeOH (65 mL), added 4N HCl (in dioxane, 2.12mL) drop wise, stirred at room temperature for 1 h, removed the solventsunder reduced pressure and finally dried under high vacuum to providehydrochloride salt in quantitative yield, which was used in the nextstep as such.

A mixture of2-chloro-5-methyl-N-[4-(2-pyridinyl)methyleneoxyphenyl]-4-pyrimidineaminehydrochloride (54 mg, 0.149 mmol) and 3-aminobenzenesulfonamide (25.6mg, 0.149 mmol) in i-PrOH (2 mL) were reacted in sealed reaction vial at100° C. for 24 hours. The product was purified by column chromatography[silica gel column, eluted with CH₂Cl₂: 2M NH₃ in MeOH (4-5%)] toprovideN2-(3-aminosulfonylphenyl)-5-methyl-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine(I-179; 55.4 mg) in 80% yield. ¹H NMR (DMSO-d₆): δ 9.23 (s, 1H), 8.57(d, 1H, J=4.5 Hz), 8.21 (s, 1H), 8.00 (m, 2H), 7.84 (s, 1H), 7.81 (dd,1H, J=1.8 and 7.8 Hz), 7.58 (d, 2H, J=8.7 Hz), 7.52 (d, 1H, J=8.1 Hz),7.33 (dd, 1H, J=5.1 and 6.9 Hz), 7.22 (m, 4H), 6.98 (d, 2H, J=8.7 Hz),5.17 (s, 2H), 2.08 (s, 3H); LCMS (m/z): 463 (MH⁺).

The following compounds were made in a similar fashion to that for1-179.

I-180:5-Methyl-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.12 (s, 1H), 8.56 (d, 1H, J=3.6 Hz), 8.17 (s, 1H),7.97 (m, 2H), 7.82 (m, 2H), 7.59 (d, 2H, J=8.7 Hz), 7.51 (d, 1H, J=7.8Hz), 7.31 (m, 2H), 7.09 (d, 1H, J=9.0 Hz), 6.98 (d, 2H, J=9.0 Hz), 5.17(s, 2H), 2.43 (s, 3H), 2.41 (d, 3H, J=4.8 Hz), 2.08 (s, 3H); LCMS (m/z):491 (MH⁺).

I-181:N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[4-(2-pyridinyl)methyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.35 (s, 1H), 8.57 (d, 1H, J=4.5 Hz), 8.30 (s, 1H),7.86-7.76 (m, 4H), 7.53 (m, 5H), 7.33 (dd, 1H, J=4.8 and 6.7 Hz), 7.09(s, 2H), 7.02 (d, 2H, J=8.7 Hz), 5.18 (s, 2H), 2.09 (s, 3H); LCMS (m/z):463 (MH⁺).

Example 40

VI-53:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamineand its prodrug

4-Nitrophenol (1.00 g, 7.19 mmol), propargyl bromide (80 wt % intoluene; 0.788 mL, 7.09 mmol), and K₂CO₃ (1.08 g, 7.84 mmol) werestirred in acetone (16.0 mL) at 60° C. for 18 h. The reaction mixturewas cooled to room temperature and diluted with water (200 mL).4-(prop-2-ynyloxy)nitrobenzene was isolated as a white solid by suctionfiltration (1.12 g). ¹H NMR (CDCl₃): δ 8.22 (d, J=9.0 Hz, 2H), 7.05 (d,J=9.0 Hz, 2H), 4.80 (d, J=2.4 Hz, 2H), 2.59 (t, J=2.4 Hz, 1H).

4-(Prop-2-ynyloxy)nitrobenzene (0.910 g, 5.13 mmol), iron (1.42 g, 25.3mmol), and NH₄Cl (0.719 g, 12.8 mmol) were vigorously stirred inEtOH/water (1:1, 55 mL) at 70° C. for 15 minutes. The reaction mixturewas filtered hot through Celite and concentrated in vacuo. The residuewas suspended in 10% 2N ammoniacal methanol in dichloromethane,sonicated, and filtered through Celite. Concentration gave4-(prop-2-ynyloxy)aniline as a brown oil which was used without furtherpurification. In general, isolated prop-2-ynyloxyanilines were unstableand were therefore used immediately after the second filtration. ¹H NMR(CDCl₃): δ 6.82 (d, J=8.7 Hz, 2H), 6.64 (d, J=8.7 Hz, 2H), 4.61 (d,J=2.4 Hz, 2H), 2.50 (t, J=2.4 Hz, 1H).

Crude 4-(prop-2-ynyloxy)aniline (0.750 g, 5.10 mmol) and2,4-dichloro-5-fluoropyrimidine (1.27 g, 0.760 mmol) were stirred inMeOH/water (4:1, 35 mL) at room temperature for 18 h. The reactionmixture was diluted with EtOAc (200 mL) and washed with 1N HCl (50 mL)and brine (50 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, hexanes ramped to EtOAc:hexanes (1:10)) to provide2-chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine as alight brown solid (0.514 g). ¹H NMR (CDCl₃): δ 8.03 (d, J=2.7 Hz, 1H),7.53 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.86 (s, 1H), 4.71 (d,J=2.4 Hz, 2H), 2.55 (t, J=2.4 Hz, 1H); LCMS: purity: 99%; MS (m/e): 279(MH⁺).

2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514g, 1.85 mmol), 3-(aminosulfonyl)-4-methylaniline (0.689 g, 3.70 mmol),and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH(6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reactionmixture was cooled to room temperature and diluted with 1N HCl (80 mL).N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine(VI-53) was isolated as a white solid by suction filtration (0.703 g).¹H NMR (DMSO-d₆): δ 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s,1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs,2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz,2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428(MH⁺).

N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine(0.200 g, 0.467 mmol), DMAP (40 mg, 0.33 mmol)) and triethylamine (0.118mL, 0.847 mmol) were stirred in THF (6.0 mL). Propionic anhydride (0.180mL, 1.40 mmol) was added to the solution dropwise. The reaction mixturewas stirred at rt overnight. The solution was diluted with ethyl acetate(50 mL) and washed with water (5×25 mL) and brine (10 mL). The organiclayer was dried (MgSO₄), filtered, and evaporated. The residue wassuspended in ethyl acetate (25 mL), sonicated and filtered off to give aprodrug of VI-53,5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine(VI-56; 0.20 g). ¹H NMR (DMSO-d₆): δ 12.01 (s, 1H), 9.44 (s, 1H), 9.26(s, 1H), 8.16 (d, J=2.4 Hz, 1H), 8.06 (dd, J=0.3 and 3.3 Hz, 1H), 8.00(dd, J=2.1 and 7.8 Hz, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.19 (d, J=8.4 Hz,1H), 6.95 (d, J=8.7 Hz, 2H), 4.77 (d, J=2.1 Hz, 2H), 3.56 (t, J=2.1 Hz,1H), 2.49 (s, 3H), 2.24 (q, J=7.2 Hz, 2H), 0.89 (t, J=7.2 Hz, 3H); LCMS:purity: 98%; MS (m/e): 484 (MH⁺).

5-Fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine(0.125 g, 0.258 mmol) was suspended in acetonitrile (1.5 mL) and water(1.5 mL) and cooled in an ice bath. A solution of 1N NaOH aq. (0.260 mL)was added dropwise. The reaction mixture was stirred until it becameclear, filtered through glass wool, and lyophilized to give the sodiumsalt of the prodrug VI-56 (independently designated as VI-62). ¹H NMR(DMSO-d₆): δ 9.17 (bs, 2H), 8.01 (d, J=3.6 Hz, 1H), 7.89 (s, 1H),7.78-7.69 (m, 3H), 6.99-6.92 (m, 3H), 4.76 (d, J=2.1 Hz, 1H), 2.43 (s,3H), 1.95 (q, J=7.2 Hz, 2H), 0.86 (t, J=7.2 Hz, 3H); LCMS: purity: 98%;MS (m/e): 484 (MH+).

The following compounds were made in a similar fashion to the example 40or by methods described herein or known to skilled artisans.

VII-31:N2-(4-Aminosulphonylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 7.93 (s, 1H), 7.60 (m, 4H), 7.24 (bs, 2H), 7.08 (m,1H), 7.02 (m, 1H) 7.27 (s, 1H), 4.61 (s, 2H), 2.14 (s, 3H); purity 99%;MS (m/e): 427 (MH⁺).

VII-33:N2-(3-Aminosulphonyl-4-methylphenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 7.91 (s, 1H), 7.80 (s, 1H), 7.66 (m, 1H), 7.48 (s,1H), 7.35 (m, 2H), 7.12 (m, 1H), 3.52 (s, 2H), 3.11 (s, 3H), 2.16 (s,3H); purity 95%; MS (m/e): 471 (MH⁺).

VII-34:N2-(4-Aminosulphonylphenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6):): δ 7.96 (s, 1H), 7.64 (m, 4H), 7.46 (s, 1H), 7.40 (s,2H), 7.18 (s, 2H), 3.53 (s, 2H), 3.26 (s, 3H), 2.16 (s, 3H); purity 90%;MS (m/e): 457 (MH⁺).

VII-32:N2-(3-Aminosulphonylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 7.91 (s, 1H), 7.82 (m, 1H), 7.65 (s, 1H), 7.51 (m,1H), 7.36 (m, 3H), 7.04 (s, 1H), 6.98 (m, 1H), 4.60 (s, 2H), 2.14 (s,3H); purity 96%; MS (m/e): 427 (MH⁺).

VII-35:N2-(3-Aminosulphonylphenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 7.95 (s, 1H), 7.73 (m, 2H), 7.38 (m, 7H), 3.52 (s,2H), 3.16 (s, 3H), 2.17 (s, 3H); purity 90%; MS (m/e): 456 (MH⁺).

VI-63:N2-[3-Aminosulfonyl-4-(2-propyl)phenyl]-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.40-9.84 (m, 2H), 8.15 (d, J=4.8 Hz, 1H), 7.89 (s,1H), 7.77 (dd, J=1.8 and 8.1 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.43 (d,J=8.7 Hz, 1H), 7.39 (s, 2H), 6.95 (d, J=9.0 Hz, 2H), 4.77 (d, J=1.8 Hz,2H), 3.77 (q, J=6.9 Hz, 1H), 3.56 (t, J=1.8 Hz, 1H), 1.20 (d, J=6.9 Hz,6H),; LCMS: purity: 98%; MS (m/e): 456 (MH⁺).

VI-64:N4-{4-[2-(Dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-N2-(3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 11.95 (s, 1H), 9.58 (s, 1H), 9.36 (s, 1H), 8.20 (s,1H), 8.12-8.04 (m, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.42-7.36 (m, 3H), 7.20(d, J=8.4 Hz, 2H), 4.15 (t, J=6.3 Hz, 2H), 2.85 (t, J=7.2 Hz, 2H), 2.79(s, 6H), 2.22 (q, J=7.5 Hz, 2H), 0.89 (t, J=7.5 Hz, 3H); LCMS: purity:97%; MS (m/e): 531 (MH⁺).

VI-65:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynylamino)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.27 (s, 1H), 9.02 (s, 1H), 8.08 (s, 1H), 7.96 (d,J=3.0 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.19 (s,2H), 7.13 (d, J=9.0 Hz, 1H), 6.63 (d, J=8.7 Hz, 2H), 5.85 (t, J=6.0 Hz,1H), 3.85 (s, 2H), 3.06-3.04 (m, 1H), 2.48 (s, 3H); LCMS: purity: 98%;MS (m/e): 427 (MH⁺).

VI-66:N4-{4-[2-(Dimethylaminocarbonyloxy)ethyl]phenyl}-5-fluoro-N2-(3-propionylaminosulfonylphenyl)-2,4-pyrimidinediaminesodium salt

¹H NMR (DMSO-d₆): δ 9.27 (s, 1H), 9.25 (s, 1H), 8.06 (d, J=3.9 Hz, 1H),7.86-7.82 (m, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.27-7.11 (m, 4H), 4.14 (t,J=6.6 Hz, 2H), 2.84 (t, J=6.6 Hz, 2H), 2.79 (s, 6H), 1.91 (q, J=7.5 Hz,2H), 0.85 (t, J=7.5 Hz, 3H),; LCMS: purity: 97%.

VI-67:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-{4-[bis(prop-2-ynyl)amino]phenyl}-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.34 (s, 1H), 9.17 (s, 1H), 8.09 (d, J=2.1 Hz, 1H),8.01 (d, J=3.6 Hz, 1H), 7.91 (dd, J=2.1 Hz, 1H), 7.63 (d, J=8.7 Hz, 2H),7.22 (s, 2H), 7.16 (d, J=8.7 Hz, 1H), 6.91 (d, J=9.3 Hz, 2H), 4.11 (d,J=2.12 Hz, 4H), 3.17 (t, J=2.1 Hz, 2H), 2.50 (s, 3H); LCMS: purity: 98%;MS (m/e): 465 (MH⁺).

VI-68:5-Fluoro-N2-(4-methyl-3-methylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.75 (s, 2H), 8.13 (d, J=3.9 Hz, 1H), 7.93-7.89 (m,1H), 7.84 (dd, J=2.4 and 8.4 Hz, 1H), 7.63 (d, J=9.0 Hz, 2H), 7.41-7.34(m, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 4.78 (d, J=2.4Hz, 2H), 3.57 (t, J=2.4 Hz, 1H), 2.49 (s, 3H), 2.40 (d, J=4.8 Hz, 3H);LCMS: purity: 96%; MS (m/e): 443 (MH⁺).

VI-69:5-Fluoro-N2-{[4-methyl-3-((1-methylpiperidin-4-yl)aminosulfonyl)]phenyl}-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.34 (s, 1H), 9.25 (s, 1H), 8.09-8.06 (m, 1H), 8.03(d, J=3.9 Hz, 1H), 7.96-7.87 (m, 1H), 7.69 (d, J=9.0 Hz, 2H), 7.67-7.63(m, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 4.77 (d, J=2.1Hz, 2H), 3.58-3.55 (m, 1H), 3.00-2.86 (m, 1H), 2.80-2.70 (m, 2H), 2.49(s, 3H), 2.20 (s, 3H), 2.13-2.99 (m, 2H), 1.66-1.40 (m, 4H); LCMS:purity: 96%; MS (m/e): 526 (MH⁺).

VI-70:N2-[3-Aminosulfonyl-4-(1-methylpiperazin-4-yl)phenyl]-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.38 (s, 1H), 9.25 (s, 1H), 8.09 (d, J=2.1 Hz, 1H),8.04 (d, J=3.6 Hz, 1H), 7.93 (dd, J=2.4 and 8.7 Hz, 1H), 7.69 (d, J=8.7Hz, 2H), 7.41 (d, J=8.7 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 6.84 (s, 2H),4.77 (d, J=2.1 Hz, 2H), 3.55 (t, J=2.1 Hz, 1H), 2.94-2.86 (m, 4H),2.53-2.44 (m, 4H), 2.25 (s, 3H); LCMS: purity: 93%; MS (m/e): 512 (MH⁺).

VI-71:N4-{4-[2-(Aminocarbonylamino)ethyl]phenyl}-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.37 (s, 1H), 9.27 (s, 1H), 8.12-8.09 (m, 1H),8.07-8.03 (m, 1H), 7.92-7.87 (m, 1H), 7.72 (d, J=7.8 Hz, 2H), 7.21 (s,2H), 7.19-7.11 (m, 3H), 5.91-5.85 (m, 1H), 5.40 (s, 2H), 3.21-3.16 (m,2H), 2.65 (t, J=7.5 Hz, 2H), 2.48 (s, 3H),; LCMS: purity: 87%; MS (m/e):461 (MH⁺).

VI-72:N4-{4-[2-(Aminocarbonylamino)ethyl]phenyl}-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.50 (s, 1H), 9.34 (s, 1H), 8.12-8.06 (m, 2H),7.98-7.94 (m, 1H), 7.71 (d, J=8.1 Hz, 2H), 7.39-7.32 (m, 2H), 7.25 (s,2H), 7.15 (d, =8.4 Hz, 2H), 5.89 (s, 1H), 3.24-3.16 (m, 2H), 2.65 (t,J=6.6 Hz, 2H),; LCMS: purity: 92%; MS (m/e): 447 (MH⁺).

VI-73:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(prop-2-ynyloxy)carbonylaminomethyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.72 (bs, 2H), 8.13 (d, J=4.2 Hz, 1H), 8.00 (s, 1H),7.93-7.86 (m, 1H), 7.82 (dd, J=2.1 and 8.1 Hz, 1H), 7.68 (d, J=8.4 Hz,2H), 7.27 (s, 2H), 7.23-7.16 (m, 3H), 4.63 (d, J=2.1 Hz, 2H), 4.16 (d,J=5.7 Hz, 2H), 3.48 (t, J=2.4 Hz, 1H), 2.42 (s, 3H); LCMS: purity: 95%;MS (m/e): 486 (MH⁺).

VI-74:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[(prop-2-ynyloxy)carbonylaminomethyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.73 (s, 1H), 9.66 (s, 1H), 8.15 (d, J=4.2 Hz, 1H),8.02 (s, 1H), 7.95-7.87 (m, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.41-7.36 (m,2H), 7.29 (s, 2H), 7.21 (d, J=8.4 Hz, 2H), 4.63 (d, J=2.1 Hz, 2H), 4.16(d, J=5.7 Hz, 2H), 3.48 (t, J=2.1 Hz, 2H); LCMS: purity: 97%; MS (m/e):471 (MH⁺).

IX-1:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.00 (s, 1H), 9.88 (s, 1H), 8.14 (d, J=4.5 Hz, 1H),7.88-7.78 (m, 3H), 7.50 (d, J=8.7 Hz, 1H), 7.41 (d, J=2.7 Hz, 1H), 7.38(dd, J=1.8 and 9.0 Hz, 1H), 7.29 (s, 2H), 7.09 (d, J=8.7 Hz, 1H), 6.43(d, J=3.0 Hz, 1H), 5.09 (d, J=2.7 Hz, 2H), 3.42 (t, J=2.7 Hz, 1H), 2.51(s, 3H); LCMS: purity: 98%; MS (m/e): 451 (MH⁺).

IX-2:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 10.03 (bs, 2H), 8.18 (d, J=4.5 Hz, 1H), 7.97-7.92(m, 1H), 7.87-7.82 (m, 2H), 7.51 (d, J=8.7 Hz, 1H), 7.42-7.36 (m, 3H),7.32-7.26 (m, 3H), 6.44 (d, J=3.3 Hz, 1H), 5.10 (d, J=2.4 Hz, 2H), 3.43(t, J=2.4 Hz, 2H); LCMS: purity: 97%; MS (m/e): 437 (MH⁺).

VI-75:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.84 (s, 1H), 9.70 (s, 1H), 8.23 (d, J=3.6 Hz, 1H),8.14-8.06 (m, 3H), 8.02 (t, J=6.0 Hz, 1H), 7.97-7.92 (m, 1H), 7.72 (d,J=8.7 Hz, 2H), 7.47-7.37 (m, 2H), 7.30 (s, 2H), 3.67 (dd, J=2.4 and 5.7Hz, 2H), 3.07 (t, J=2.4 Hz, 1H); LCMS: purity: 96%; MS (m/e): 478 (MH⁺).

VI-76:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.86 (s, 1H), 9.64 (s, 1H), 8.21 (d, J=3.9 Hz, 1H),8.13-8.08 (m, 2H), 8.06-8.00 (m, 2H), 7.87 (dd, J=2.4 and 8.4 Hz, 1H),7.70 (d, J=8.7 Hz, 2H), 7.28 (s, 2H), 7.23 (d, J=8.4 Hz, 1H), 3.67 (dd,J=2.4 and 6.0 Hz, 2H), 3.07 (t, J=2.7 Hz, 1H), 2.52 (s, 3H); LCMS:purity: 96%; MS (m/e): 492 (MH⁺).

VI-77:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.89 (s, 1H), 9.81 (s, 1H), 8.26 (d, J=3.3 Hz, 1H),8.10-8.03 (m, 3H), 7.84 (d, J=9.0, 2H), 7.73 (d, J=9.0 Hz, 2H), 7.68 (d,J=9.0 Hz, 2H), 7.17 (s, 2H), 3.68 (dd, J=2.7 and 5.7 Hz, 2H), 3.06 (t,J=2.7 Hz, 1H); LCMS: purity: 96 MS (m/e): 477(MH⁺).

VI-78:5-Fluoro-N2-[3-(prop-2-ynylaminosulfonyl)phenyl]-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.76 (s, 1H), 9.66 (s, 1H), 8.14 (d, J=4.2 Hz, 1H),8.07 (t, J=6.3 Hz, 1H), 7.99-7.94 (m, 2H), 7.64 (d, J=9.0 Hz, 2H),7.45-7.32 (m, 2H), 6.96 (d, J=9.0 Hz, 2H), 4.78 (d, J=1.8 Hz, 2H),3.67-3.63 (m, 2H), 3.62-3.56 (m, 1H); LCMS: purity: 96%; MS (m/e): 452(MH⁺).

IX-3:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-6-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.90 (s, 1H), 9.74 (s, 1H), 8.13 (d, J=4.2 Hz, 1H),7.96 (s, 1H), 7.86-7.79 (m, 2H), 7.52 (d, J=8.1 Hz, 1H), 7.40-7.36 (m,2H), 7.27 (s, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.45 (d, J=3.0 Hz, 1H), 5.01(d, J=2.4 Hz, 1H), 3.38 (t, J=2.4 Hz, 1H), 2.49 (s, 3H); LCMS: purity:91%; MS (m/e): 451 (MH⁺).

IX-4:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-6-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.70-9.58 (m, 2H), 8.12 (d, J=3.9 Hz, 1H), 8.02 (s,1H), 7.95 (d, J=7.8 Hz, 1H), 7.85 (s, 1H), 7.52 (d, J=9.0 Hz, 1H),7.42-7.25 (m, 6H), 6.44 (d, J=2.7 Hz, 1H), 5.03 (s, 2H), 3.38 (m, 1H);LCMS: purity: 92%; MS (m/e): 437 (MH⁺).

VI-79:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.92 (s, 1H), 9.64 (s, 1H), 8.32 (d, J=7.5 Hz, 1H),8.19 (d, J=3.9 Hz, 1H), 8.14 (d, J=6.0 Hz, 1H), 8.06-8.03 (m, 1H),8.00-7.97 (m, 1H), 7.81 (dd, J=2.1 and 8.4 Hz, 1H), 7.57-7.46 (m, 2H),7.27 (s, 2H), 7.22 (d, J=8.7 Hz, 1H), 3.69 (dd, J=2.4 and 5.7 Hz, 2H),3.06 (t, J=2.7 Hz, 1H), 2.44 (s, 3H); LCMS: purity: 96%; MS (m/e): 492(MH⁺).

VI-80:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.77 (s, 1H), 9.63 (s, 1H), 8.33-8.27 (m, 1H), 8.21(d, J=3.6 Hz, 1H), 8.15 (t, J=6.3 Hz, 1H), 7.99-7.96 (m, 1H), 7.79 (d,J=8.7 Hz, 2H), 7.64 (d, J=9.0 Hz, 2H), 7.59-7.48 (m, 2H), 7.12 (s, 2H),3.71 (dd, J=2.4 and 5.7 Hz, 2H), 3.06 (t, J=2.4 Hz, 1H); LCMS: purity:95%; MS (m/e): 477 (MH⁺).

VI-81:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.80 (s, 1H), 9.60 (s, 1H), 8.39-8.34 (m, 1H), 8.20(d, J=3.6 Hz, 1H), 8.15 (t, J=6.0 Hz, 1H), 8.10-8.06 (m, 1H), 8.02-7.98(m, 1H), 7.94-7.88 (m, 1H), 7.54 (t, J=8.1 Hz, 1H), 7.49-7.34 (m, 3H),7.28 (s, 2H), 3.70 (dd, J=2.4 and 5.4 Hz, 2H), 3.07 (t, J=2.4 Hz, 1H);LCMS: purity: 98%; MS (m/e): 477 (MH⁺).

III-84:N2-[4-(2-N,N-Diethylaminoethyl)aminosulfonylphenyl)-5-fluoro-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.64 (s, 1H), 9.49 (s, 1H), 8.15 (d, 2H,J=3.6 Hz), 7.81 (d, 2H, J=8.4 Hz), 7.76 (s, 1H), 7.70 (d, 2H, J=8.1 Hz),7.55 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.20 (s, 1H), 5.17 (s,2H), 2.76 (t, 2H, J=7.2 Hz), 2.42 (m, 6H), 0.87 (t, 6H, J=7.2 Hz); LCMS(m/z): 539 (MH⁺).

III-76:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)phenethyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.48 (s, 1H), 9.29 (s, 1H), 8.41 (d, 2H,J=5.1 Hz), 8.09 (d, 2H, J=2.4 Hz), 7.95 (m, 1H), 7.69 (d, 2H, J=8.4 Hz),7.34 (d, 2H, J=5.1 Hz), 7.24 (d, 4H, J=6.0 Hz), 7.16 (d, 2H, J=8.4 Hz),3.30 (d, 4H, J=1.2 Hz); LCMS (m/z): 465 (MH⁺).

III-77:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)phenethyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.38 (s, 1H), 9.26 (s, 1H), 8.41 (d, 2H,J=4.5 Hz), 8.10 (s, 1H), 8.05 (d, 1H, J=3.3 Hz), 7.89 (d, 1H, J=8.1 Hz),7.80 (d, 2H, J=7.8 Hz), 7.23 (m, 4H), 7.15 (m, 3H), 3.31 (d, 4H, J=1.2Hz), 2.48 (s, 3H); LCMS (m/z): 479 (MH⁺).

III-78:5-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(4-pyridinyl)phenethyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.38 (s, 1H), 9.27 (s, 1H), 8.41 (d, 2H,J=5.1 Hz), 8.07 (d, 2H, J=3.9 Hz), 8.01 (s, 1H), 7.93 (m, 1H), 7.69 (d,2H, J=8.4 Hz), 7.32 (q, 1H, J=4.8 Hz), 7.23 (d, 2H, J=5.4 Hz), 7.17 (t,3H, J=8.1 Hz), 3.30 (s, 4H), 2.46 (s, 3H), 2.42 (d, 3H, J=4.5 Hz); LCMS(m/z): 493 (MH⁺).

I-169:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-fluoromethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.56 (s, 1H), 9.40 (s, 1H), 8.56 (m, 1H),8.11 (d, 1H, J=3.9 Hz), 8.08 (s, 1H), 7.95 (m, 1H), 7.88 (m, 1H), 7.84(m, 2H), 7.52 (d, 1H, J=7.5 Hz), 7.48 (s, 1H), 7.35 (m, 2H), 7.26 (s,2H), 7.16 (t, 1H, J=9.3 Hz), 5.23 (s, 2H); LCMS (m/z): 485 (MH⁺).

I-170:5-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(2-pyridinyl)-3-methylmethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.32 (s, 1H), 9.15 (s, 1H), 8.57 (m, 1H),8.03 (d, 1H, J=3.9 Hz), 7.94 (m, 2H), 7.83 (m, 1H), 7.52 (m, 3H), 7.33(m, 2H), 7.14 (d, 1H, J=8.7 Hz), 6.93 (d, 1H, J=9.6 Hz), 5.18 (s, 2H),2.45 (s, 3H), 2.41 (d, 3H, J=4.2 Hz), 2.25 (s, 3H); LCMS (m/z): 509(MH⁺).

I-171:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-chloromethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.53 (s, 1H), 9.37 (s, 1H), 8.57 (m, 1H),8.10 (d, 1H, J=3.6 Hz), 8.03 (s, 1H), 7.96 (m, 1H), 7.85 (m, 2H), 7.72(dd, 1H, J=2.4 and 9.0 Hz), 7.55 (d, 1H, J=8.1 Hz), 7.35 (m, 3H), 7.25(s, 2H), 7.17 (d, 1H, J=9.3 Hz), 5.27 (s, 2H); LCMS (m/z): 501 (MH⁺).

I-172:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-fluoromethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.44 (s, 1H), 9.37 (s, 1H), 8.56 (d, 1H,J=3.9 Hz), 8.09 (s, 1H), 8.07 (d, 1H, J=3.6 Hz), 7.90-7.81 (m, 3H), 7.51(t, 2H, J=7.5 Hz), 7.34 (m, 1H), 7.24 (s, 1H), 7.15 (m, 2H), 5.23 (s,2H), 2.49 (s, 3H); LCMS (m/z): 449 (MH⁺).

I-173:5-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(2-pyridinyl)-3-fluoromethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.48 (s, 1H), 9.38 (s, 1H), 8.57 (m, 1H),8.08 (d, 1H, J=3.0 Hz), 8.01 (s, 1H), 7.95 (dd, 1H, J=2.1 and 8.4 Hz),7.83 (m, 2H), 7.51 (t, 2H, J=9.3 Hz), 7.35 (m, 2H), 7.19 (d, 1H, J=8.1Hz), 7.14 (d, 1H, J=9.3 Hz), 5.23 (s, 2H), 2.46 (s, 3H), 2.41 (d, 1H,J=4.2 Hz),; LCMS (m/z): 513 (MH⁺).

I-174:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-chloromethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.42 (s, 1H), 9.34 (s, 1H), 8.57 (d, 1H,J=3.6 Hz), 8.07 (m, 1H), 7.86 (m, 3H), 7.73 (d, 1H, J=9.0 Hz), 7.55 (d,1H, J=7.5 Hz), 7.34 (t, 1H, J=5.1 Hz), 7.24 (s, 2H), 7.16 (d, 2H, J=8.7Hz), 5.26 (s, 2H), 2.49 (s, 3H); LCMS (m/z): 515 (MH⁺).

IX-54:5-Fluoro-N2-[3-N-(methyl)aminosulfonyl-4-methylphenyl]-N4-[4-(2-pyridinyl)-3-chloromethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.43 (s, 1H), 9.35 (s, 1H), 8.56 (m, 1H),8.09 (d, 1H, J=3.0 Hz), 7.96 (m, 2H), 7.85 (m, 2H), 7.71 (dd, 1H, J=3.0and 8.8 Hz), 7.55 (d, 1H, J=7.8 Hz), 7.34 (t, 2H, J=5.1 Hz), 7.17 (t,2H, J=9.0 Hz), 5.26 (s, 2H), 2.45 (s, 3H), 2.41 (d, 1H, J=4.8 Hz),; LCMS(m/z): 529 (MH⁺).

II-11:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.57 (s, 1H), 9.52 (s, 1H), 8.43 (s, 1H),8.39 (t, 1H, J=2.1 Hz), 8.18 (t, 2H, J=3.3 Hz), 7.99 (d, 1H, J=7.5 Hz),7.93 (d, 2H, J=8.7 Hz), 7.44 (m, 4H), 7.32 (s, 2H), 7.13 (d, 2H, J=9.0Hz); LCMS (m/z): 453 (MH⁺).

III-85:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediaminehydrochloride

¹H NMR (DMSO d₆, 300 MHz): δ 9.79 (s, 1H), 9.75 (s, 1H), 9.30 (s, 1H),8.18 (d, 1H, J=3.0 Hz), 7.94 (s, 1H), 7.86 (d, 1H, J=8.1 Hz), 7.80 (d,3H, J=8.1 Hz), 7.69 (s, 1H), 7.38 (d, 3H, J=8.4 Hz), 7.20 (d, 1H, J=8.4Hz), 5.40 (s, 2H), 2.48 (s, 3H), 2.39 (d, 3H, J=4.2 Hz); LCMS (m/z): 468(MH⁺).

III-86:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1-imidazolylmethyl)phenyl]-2,4-pyrimidinediaminedihydrochloride

¹H NMR (DMSO d₆, 300 MHz): δ 9.85 (s, 1H), 9.81 (s, 1H), 9.31 (s, 1H),8.19 (d, 1H, J=4.2 Hz), 7.93 (s, 1H), 7.84 (d, 1H, J=8.1 Hz), 7.80 (d,3H, J=8.1 Hz), 7.69 (s, 1H), 7.38 (d, 3H, J=8.4 Hz), 7.20 (d, 1H, J=8.4Hz), 5.41 (s, 2H), 2.48 (s, 3H), 2.39 (d, 3H, J=4.2 Hz); LCMS (m/z): 468(MH⁺).

II-12:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.42 (s, 1H), 9.40 (s, 1H), 8.32 (m, 2H),8.08 (d, 2H, J=3.0 Hz), 7.86 m, 2H), 7.39 (m, 2H), 7.23 (s, 2H), 7.09(m, 4H), 2.36 (s, 3H), 7.13; LCMS (m/z): 467 (MH⁺).

II-13:5-Fluoro-N2-[3-N-(methylaminosulfonyl)-4-methylphenyl]-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.43 (s, 1H), 9.40 (s, 1H), 8.35 (s, 1H),8.32 (t, 1H, J=2.4 Hz), 8.09 (d, 1H, J=3.6 Hz), 8.00 (s, 1H), 7.93 (dd,1H, J=1.8 and 8.2 Hz), 7.84 (d, 2H, J=8.7 Hz), 7.39 (m, 2H), 7.33 (q,1H, J=4.2 Hz), 7.18 (d, 1H, J=8.4 Hz), 7.06 (d, 2H, J=8.7 Hz), 2.44 (s,3H), 2.40 (d, 3H, J=4.5 Hz),; LCMS (m/z): 481 (MH⁺).

III-79:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(4-pyridinyl)phenethyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.56 (s, 1H), 9.37 (s, 1H), 8.42 (d, 2H,J=4.2 Hz), 8.11 (d, 1H, J=3.6 Hz), 7.79 (d, 2H, J=8.4 Hz), 7.61 (t, 4H,J=9.3 Hz), 7.24 (d, 2H, J=5.1 Hz), 7.19 (d, 4H, J=8.1 Hz), 7.15 (s, 2H),3.92 (s, 4H); LCMS (m/z): 465 (MH⁺).

I-175:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-chloromethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.71 (s, 1H), 9.51 (s, 1H), 8.64 (d, 1H,J=4.1 Hz), 8.20 (d, 1H, J=3.6 Hz), 7.92 (m, 2H), 7.85 (d, 2H, J=8.7 Hz),7.71 (d, 2H, J=9.3 Hz), 7.63 (d, 2H, J=8.7 Hz), 7.41 (m, 1H), 7.26 (d,1H, J=9.3 Hz), 7.19 (s, 2H), 5.33 (s, 2H); LCMS (m/z): 501 (MH⁺).

I-176:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-methylmethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.63 (s, 1H), 9.33 (s, 1H), 8.63 (m, 1H),8.15 (d, 1H, J=3.9 Hz), 7.91 (t, 1H, J=7.8 Hz), 7.85 (d, 2H, J=8.7 Hz),7.66 (d, 2H, J=8.4 Hz), 7.60 (m, 2H), 7.42 (m, 2H), 7.19 (s, 2H), 7.03(d, 1H, J=8.4 Hz), 5.26 (s, 2H), 2.34 (s, 3H); LCMS (m/z): 481 (MH⁺).

II-14:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.67 (s, 1H), 9.58 (s, 1H), 8.41 (d, 2H,J=12.3 Hz), 8.21 (d, 1H, J=3.3 Hz), 7.86 (d, 4H, J=6.9 Hz), 7.68 (d, 2H,J=9.0 Hz), 7.48 (s, 2H), 7.17 (m, 4H); LCMS (m/z): 453 (MH⁺).

III-87:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-imidazolyl)phenethyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.51 (s, 1H), 9.32 (s, 1H), 8.09 (d, 2H,J=3.6 Hz), 7.94 (s, 1H), 7.71 (d, 2H, J=8.4 Hz), 7.48 (s, 1H), 7.35 (m,2H), 7.26 (s, 2H), 7.14 (s, 1H), 7.10 (d, 2H, J=8.4 Hz), 6.83 (s, 1H),4.26 (t, 2H, J=6.9 Hz), 3.06 (t, 2H, J=7.2 Hz); LCMS (m/z): 454 (MH⁺).

III-88:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1-imidazolyl)phenethyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.47 (s, 1H), 9.35 (s, 1H), 8.17 (s, 1H),8.13 (d, 1H, J=3.0 Hz), 7.95 (dd, 1H, J=2.1 and 8.1 Hz), 7.78 (d, 2H,J=8.1 Hz), 7.54 (s, 1H), 7.29 (s, 2H), 7.24 (d, 1H, J=8.1 Hz), 7.20 (s,2H), 7.16 (d, 2H, J=8.4 Hz), 6.90 (s, 1H), 4.26 (t, 2H, J=6.9 Hz), 3.06(t, 2H, J=7.2 Hz), 2.53 (s, 3H); LCMS (m/z): 468 (MH⁺).

III-91:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(2-methyl-1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.39 (s, 2H), 8.08 (d, 1H, J=3.0 Hz), 7.89(s, 1H), 7.87 (dd, 1H, J=2.1 and 8.2 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.24(s, 1H), 7.15 (s, 1H), 7.11 (d, 2H, J=8.4 Hz), 6.79 (s, 1H), 5.10 (s,2H), 2.49 (s, 3H), 2.26 (s, 3H); LCMS (m/z): 468 (MH⁺).

III-89:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1-imidazolyl)phenethyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.40 (s, 1H), 9.29 (s, 1H), 8.08 (d, 1H,J=3.9 Hz), 8.02 (d, 1H, J=2.1 Hz), 7.95 (dd, 1H, J=1.8 and 8.4 Hz), 7.71(d, 2H, J=8.4 Hz), 7.48 (s, 1H), 7.33 (q, 1H, J=4.5 Hz), 7.20 (d, 1H,J=8.4 Hz), 7.14 (s, 1H), 7.10 (d, 2H, J=8.4 Hz), 6.84 (s, 1H), 4.19 (t,2H, J=7.2 Hz), 3.00 (t, 2H, J=7.2 Hz), 2.46 (s, 3H), 2.42 (d, 3H, J=4.8Hz),; LCMS (m/z): 482 (MH⁺).

I-177:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-pyridinyl)-3-fluoromethyleneoxyphenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.72 (s, 1H), 9.54 (s, 1H), 8.64 (d, 1H,J=4.8 Hz), 8.21 (d, 1H, J=3.6 Hz), 7.92 (m, 2H), 7.88 (d, 2H, J=8.4 Hz),7.70 (d, 2H, J=8.7 Hz), 7.60 (d, 1H, J=8.1 Hz), 7.50 (d, 1H, J=8.7 Hz),7.41 (dd, 1H, J=5.1 and 6.7 Hz), 7.26 (t, 1H, J=9.3 Hz), 7.21 (s, 2H),5.31 (s, 2H); LCMS (m/z): 485 (MH⁺).

III-92:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methyl-1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.60 (s, 1H), 9.49 (s, 1H), 8.13 (t, 2H,J=3.6 Hz), 7.77 (d, 1H, J=9.0 Hz), 7.70 (d, 2H, J=8.4 Hz), 7.55 (d, 2H,J=8.7 Hz), 7.27 (s, 2H), 7.15 (s, 1H), 7.17 (s, 1H), 7.12 (d, 2H, J=8.4Hz), 6.79 (s, 1H), 5.13 (s, 2H), 2.24 (s, 3H); LCMS (m/z): 454 (MH⁺).

III-99:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-{4-[1-(1,2,4-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.60 (s, 1H), 9.49 (s, 1H), 8.64 (s, 1H),8.15 (d, 1H, J=3.6 Hz), 7.98 (s, 1H), 7.80 (d, 2H, J=8.7 Hz), 7.74 (d,2H, J=8.4 Hz), 7.62 (d, 2H, J=8.7 Hz), 7.27 (d, 2H, J=8.7 Hz), 7.14 (s,2H), 5.39 (s, 2H); LCMS (m/z): 441 (MH⁺).

III-95:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.41 (s, 1H), 9.40 (s, 1H), 8.17 (s, 1H),8.09 (d, 2H, J=3.6 Hz), 7.86 (dd, 1H, J=2.1 and 8.2 Hz), 7.79 (d, 2H,J=8.4 Hz), 7.73 (s, 1H), 7.26 (d, 2H, J=8.7 Hz), 7.24 (s, 1H), 7.12 (d,1H, J=8.1 Hz), 5.74 (s, 2H), 2.48 (s, 3H); LCMS (m/z): 455 (MH⁺).

III-96:N2-4-Aminosulfonylphenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.60 (s, 1H), 9.51 (s, 1H), 8.17 (d, 1H,J=0.9 Hz), 8.15 (d, 1H, J=3.6 Hz), 7.78 (t, 3H, J=5.4 Hz), 7.74 (s, 2H),7.61 (d, 2H, J=8.7 Hz), 7.29 (d, 2H, J=8.4 Hz), 7.15 (s, 2H), 5.59 (s,2H); LCMS (m/z): 441 (MH⁺).

III-100:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[1-(1,2,4-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.50 (s, 1H), 9.44 (s, 1H), 8.64 (s, 1H),8.63 (s, 1H), 8.11 (d, 1H, J=3.9 Hz), 8.09 (s, 1H), 7.97 (s, 1H), 7.93(bs s, 1H), 7.78 (d, 2H, J=8.4 Hz), 7.33 (d, 2H, J=4.8 Hz), 7.26 (d, 4H,J=7.5 Hz), 5.37 (s, 2H); LCMS (m/z): 441 (MH⁺).

III-101:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[1-(1,2,4-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.46 (s, 2H), 8.70 (s, 1H), 8.15 (d, 1H,J=3.3 Hz), 8.04 (s, 1H), 7.94 (dd, 1H, J=2.4 and 8.4 Hz), 7.84 (d, 2H,J=8.4 Hz), 7.30 (m, 3H), 7.19 (s, 1H), 7.17 (s, 1H), 5.44 (s, 2H), 2.55(s, 3H); LCMS (m/z): 455 (MH⁺).

III-102:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-{4-[1-(1,2,4-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.42 (s, 1H), 9.40 (s, 1H), 8.64 (s, 1H),8.09 (d, 1H, J=3.6 Hz), 8.01 (d, 1H, J=1.8 Hz), 7.97 (s, 1H), 7.93 (dd,1H, J=2.4 and 8.1 Hz), 7.77 (d, 2H, J=8.7 Hz), 7.34 (q, 1H, J=4.8 Hz),7.24 (d, 2H, J=8.4 Hz), 7.15 (d, 1H, J=8.4 Hz), 5.38 (s, 2H), 2.46 (s,3H), 2.41 (d, 3H, J=4.8 Hz),; LCMS (m/z): 469 (MH⁺).

VII-60:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-methylsulfonyl)indolin-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.47 (s, 1H), 9.36 (s, 1H), 8.09 (d, 1H,J=3.3 Hz), 8.06 (s, 1H), 7.95 (d, 1H, J=7.8 Hz), 7.73 (s, 1H), 7.59 (d,1H, J=8.4 Hz), 7.35 (m, 2H), 7.25 (s, 2H), 7.20 (d, 1H, J=8.4 Hz), 3.94(t, 2H, J=8.7 Hz), 3.11 (t, 2H, J=8.1 Hz), 2.97 (s, 3H); LCMS (m/z): 479(MH⁺).

VII-61:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1-methylsulfonyl)indolin-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.35 (s, 1H), 9.31 (s, 1H), 8.06 (m, 2H),7.87 (dd, 1H, J=2.1 and 8.1 Hz), 7.72 (s, 1H), 7.58 (d, 1H, J=10.5 Hz),7.18 (m, 4H), 3.94 (t, 2H, J=8.7 Hz), 3.10 (t, 2H, J=8.4 Hz), 2.96 (s,3H), 2.48 (s, 3H); LCMS (m/z): 493 (MH⁺).

VII-62:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1-methylsulfonyl)indolin-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.36 (s, 1H), 9.33 (s, 1H), 8.07 (d, 1H,J=3.6 Hz), 7.99 (d, 1H, J=2.1 Hz), 7.93 (dd, 1H, J=2.4 and 8.2 Hz), 7.71(s, 1H), 7.57 (dd, 1H, J=2.1 and 8.7 Hz), 7.33 (q, 1H, J=4.8 Hz), 7.19(d, 2H, J=8.4 Hz), 3.94 (t, 2H, J=8.7 Hz), 3.10 (t, 2H, J=8.4 Hz), 2.96(s, 3H), 2.46 (s, 3H), 2.41 (d, 3H, J=4.8 Hz); LCMS (m/z): 507 (MH⁺).

III-93:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(2-methyl-1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.39 (s, 2H), 8.09 (d, 1H, J=3.3 Hz), 8.00(d, 1H, J=2.1 Hz), 7.92 (dd, 1H, J=2.4 and 8.1 Hz), 7.33 (q, 1H, J=5.1Hz), 7.12 (m, 4H), 6.75 (s, 1H), 5.09 (s, 2H), 2.46 (s, 3H), 2.41 (d,3H, J=4.5 Hz), 2.24 (s, 3H); LCMS (m/z): 482 (MH⁺).

III-97:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.58 (s, 1H), 9.52 (s, 1H), 8.24 (s, 1H),8.18 (d, 1H, J=3.6 Hz), 8.17 (s, 1H), 7.98 (m, 1H), 7.86 (d, 2H, J=8.7Hz), 7.80 (s, 1H), 7.40 (d, 2H, J=4.8 Hz), 7.33 (m, 4H), 5.64 (s, 2H);LCMS (m/z): 441 (MH⁺).

III-98:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-{4-[1-(1,2,3-triazolyl)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.43 (s, 1H), 9.41 (s, 1H), 8.17 (d, 1H,J=0.9 Hz), 8.09 (d, 1H, J=3.9 Hz), 8.00 (d, 1H, J=2.1 Hz), 7.92 (dd, 1H,J=2.4 and 8.1 Hz), 7.76 (t, 3H, J=8.7 Hz), 7.33 (q, 1H, J=5.1 Hz), 7.26(d, 2H, J=9.0 Hz), 7.14 (d, 1H, J=8.4 Hz), 5.58 (s, 2H), 2.46 (s, 3H),2.41 (d, 3H, J=4.8 Hz); LCMS (m/z): 469 (MH⁺).

III-90:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-imidazolyl)phenethyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.61 (s, 1H), 9.38 (s, 1H), 8.13 (d, 1H,J=3.9 Hz), 7.79 (d, 2H, J=8.7 Hz), 7.62 (t, 4H, J=9.0 Hz), 7.51 (s, 1H),7.23 (s, 1H), 7.15 (s, 1H), 7.12 (d, 2H, J=8.4 Hz), 6.85 (s, 1H), 4.21(t, 2H, J=6.9 Hz), 3.03 (t, 2H, J=6.9 Hz); LCMS (m/z): 454 (MH⁺).

VII-63:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1-methylsulfonyl)indolin-5-yl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.57 (s, 1H), 9.41 (s, 1H), 8.11 (d, 1H,J=3.6 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.68 (s, 1H), 7.60 (d, 1H, J=8.4 Hz),7.50 (d, 1H, J=8.4 Hz), 7.22 (d, 1H, J=9.0 Hz), 7.13 (s, 2H), 3.95 (t,2H, J=5.4 Hz), 3.12 (t, 2H, J=8.1 Hz), 2.97 (s, 3H); LCMS (m/z): 479(MH⁺).

IV-5:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.58 (s, 1H), 9.57 (s, 1H), 8.39 (s, 1H),8.16 (d, 1H, J=3.6 Hz), 8.13 (s, 1H), 7.97 (d, 2H, J=8.7 Hz), 7.93 (s,1H), 7.67 (d, 2H, J=8.4 Hz), 7.59 (s, 1H), 7.39 (m, 2H), 7.27 (s, 2H);LCMS (m/z): 427 (MH⁺).

IV-6:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.58 (s, 1H), 9.52 (s, 1H), 8.45 (s, 1H),8.19 (t, 2H, J=3.9 Hz), 8.04 (d, 2H, J=8.4 Hz), 7.95 (dd, 1H, J=2.1 and8.4 Hz), 7.72 (d, 2H, J=8.7 Hz), 7.65 (s, 1H), 7.30 (s, 2H), 7.27 (d,1H, J=8.4 Hz), 2.57 (s, 3H); LCMS (m/z): 441 (MH⁺).

IV-1:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.61 (s, 1H), 9.59 (s, 1H), 8.47 (s, 1H),8.22 (d, 1H, J=3.0 Hz), 8.10 (d, 2H, J=9.9 Hz), 8.04 (d, 1H, J=7.8 Hz),7.97 (m, 1H), 7.70 (s, 1H), 7.50 (d, 2H, J=4.8 Hz), 7.31 (m, 4H); LCMS(m/z): 427 (MH⁺).

IV-2:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.55 (s, 1H), 9.50 (s, 1H), 8.46 (s, 1H),8.18 (d, 1H, J=3.6 Hz), 8.12 (d, 1H, J=2.1 Hz), 8.09 (s, 1H), 7.95 (m,2H), 7.69 (s, 1H), 7.49 (d, 2H, J=5.1 Hz), 7.29 (s, 2H), 7.06 (d, 1H,J=8.1 Hz), 2.52 (s, 3H); LCMS (m/z): 441 (MH⁺).

IV-7:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[4-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.54 (s, 1H), 9.48 (s, 1H), 8.39 (s, 1H),8.13 (d, 1H, J=3.6 Hz), 8.06 (d, 1H, J=2.4 Hz), 7.97 (d, 2H, J=8.7 Hz),7.92 (d, 1H, J=2.4 Hz), 7.66 (d, 2H, J=8.7 Hz), 7.59 (s, 1H), 7.33 (q,1H, J=4.8 Hz), 7.24 (d, 1H, J=8.4 Hz), 2.47 (s, 3H), 2.42 (d, 3H, J=4.8Hz),; LCMS (m/z): 455 (MH⁺).

IV-8:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.65 (s, 1H), 9.59 (s, 1H), 8.41 (s, 1H),8.18 (d, 1H, J=3.6 Hz), 7.98 (s, 1H), 7.81 (m, 4H), 7.64 (s, 1H), 7.55(d, 2H, J=9.0 Hz), 7.47 (m, 1H); LCMS (m/z): 427 (MH⁺).

IV-3:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.68 (s, 1H), 9.62 (s, 1H), 8.40 (s, 1H),8.19 (d, 1H, J=3.6 Hz), 7.93 (d, 2H, J=8.7 Hz), 7.83 (d, 2H, J=8.7 Hz),7.66 (m, 5H), 7.13 (s, 2H); LCMS (m/z): 427 (MH⁺).

IV-4:5-Fluoro-N2-[3-(N-methylaminosulfony)-4-methylphenyl]-N4-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.51 (s, 1H), 9.45 (s, 1H), 8.39 (s, 1H),8.14 (d, 1H, J=3.6 Hz), 8.02 (s, 1H), 7.97-7.85 (m, 3H), 7.61 (s, 1H),7.43 (d, 2H, J=5.1 Hz), 7.33 (q, 1H, J=4.8 Hz), 7.03 (d, 1H, J=8.1 Hz),2.41 (d, 6H, J=4.8 Hz); LCMS (m/z): 455 (MH⁺).

II-15:N2-[3,5-bis(Aminosulfonyl)phenyl)-5-fluoro-N4-[4-(3-pyridyloxy)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.84 (s, 1H), 9.52 (s, 1H), 8.40 (d, 1H,J=1.5 Hz), 8.34 (m, 2H), 8.16 (t, 2H, J=3.6 Hz), 7.93 (d, 2H, J=8.7 Hz),7.79 (t, 1H, J=1.5 Hz), 7.50 (s, 4H), 7.39 (m, 2H), 7.06 (d, 2H, J=9.0Hz); LCMS (m/z): 532 (MH⁺).

III-94:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-methyl-1-imidazolylmethyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.48 (s, 1H), 9.41 (s, 1H), 8.10 (t, 2H,J=3.9 Hz), 7.92 (m, 1H), 7.78 (d, 2H, J=8.4 Hz), 7.33 (d, 2H, J=4.8 Hz),7.25 (s, 2H), 7.11 (d, 3H, J=8.4 Hz), 6.76 (s, 1H), 5.09 (s, 2H), 2.24(s, 3H); LCMS (m/z): 454 (MH⁺).

I-192:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridinyl)-methylenethiophenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO d₆, 300 MHz): δ 9.60 (s, 1H), 9.49 (s, 1H), 8.48 (s, 1H),8.45 (d, 1H, J=4.8 Hz), 8.19 (d, 1H, J=3.9 Hz), 8.16 (s, 1H), 7.98 (m,1H), 7.86 (d, 2H, J=9.0 Hz), 7.74 (d, 1H, J=7.8 Hz), 7.42 (m, 2H), 7.34(m, 4H), 7.18 (s, 2H), 4.26 (s, 2H); LCMS (m/z): 483 (MH⁺).

VI-94:N2-(4-aminosulfonyl)phenyl-5-fluoro-N4-(4-thiomethylcarbonyl)phenyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.81 (t, J=7.5 Hz, 1H), 3.74 (d, J=7.5 Hz, 2H), 7.11(br, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.1Hz, 2H), 7.80 (d, J=9.3 Hz, 2H), 8.13 (d, J=3.6 Hz, 1H), 9.42 (br, 1H),9.59 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.61; LCMS: purity:79.54%; MS (m/e): 406.05 (M-28).

VI-95:N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-N4-(4-thiomethylcarbonyl)phenyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.50 (s, 3H), 2.82 (t, J=7.5 Hz, 1H), 3.72 (d, J=7.2Hz, 2H), 7.18 (d, J=8.7 Hz, 1H), 7.23 (br, 2H), 7.28 (d, J=8.4 Hz, 2H),7.73 (d, J=8.7 Hz, 2H), 7.90 (dd, J=8.4 Hz, 1H), 8.07 (d, J=3.9 Hz, 1H),8.11 (d, J=2.1 Hz, 1H), 9.33 (br, 1H), 9.40 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.55; LCMS: purity: 98.63%; MS (m/e): 420.06 (M-28).

III-41:N2-(4-aminosulfonyl)phenyl-N4-(4-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.65-0.72 (m, 4H), 1.61 (m, 1H), 4.26 (d, J=6.3 Hz,2H), 7.12 (br, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.70(d, J=8.1 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 8.13 (d, J=3.9 Hz, 1H), 8.54(t, J=5.7 Hz, 1H), 9.42 (br, 1H), 9.58 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.16; LCMS: purity: 98.07%; MS (m/e): 457.29 (MH+).

III-42:N2-(3-aminosulfonyl)phenyl-N4-(4-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.65-0.72 (m, 4H), 1.60 (m, 1H), 4.24 (d, J=6.0 Hz,2H), 7.20 (d, J=8.7 Hz, 2H), 7.26 (br, 2H), 7.35 (m, 2H), 7.71 (d, J=8.4Hz, 2H), 7.94 (dt, 2.1, 6.6 Hz, 1H), 8.06 (s, 1H), 8.11 (d, J=3.6 Hz,1H), 8.52 (t, J=6.0 Hz, 1H), 9.47 (br, 1H), 9.56 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.79; LCMS: purity: 96.52%; MS (m/e): 457.46 (MH+).

III-43:N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(4-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.66-0.72 (m, 4H), 1.63 (m, 1H), 2.52 (s, 3H), 4.25(d, J=5.7 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.22 (d, J=2.1 Hz, 1H), 7.28(br, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.81 (dd, J=2.4, 8.1 Hz, 1H), 7.97 (s,1H), 8.15 (d, J=4.2 Hz, 1H), 8.54 (t, J=5.7 Hz, 1H), 9.80 (br, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ −201.18; LCMS: purity: 99.45%; MS (m/e):471.57 (MH+).

III-125:N2-(4-aminosulfonyl)phenyl-N4-[4-(N-carbamoyl-N-propyl)aminomethyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.91 (t, J=7.5 Hz, 3H), 1.65 (q, J=7.5 Hz, 2H), 2.84(m, 2H), 4.11 (s, 2H), 7.14 (br, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.66 (d,J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 8.19 (d,J=3.6 Hz, 1H), 8.87 (br, 2H), 9.55 (br, 1H), 9.67 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.11; LCMS: purity: 100%; MS (m/e): 431.45 (M-42).

III-126:N2-(3-aminosulfonyl)phenyl-N4-[4-(N-carbamoyl-N-propyl)aminomethyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.91 (t, J=7.2 Hz, 3H), 1.65 (q, J=7.5 Hz, 2H), 2.84(m, 2H), 4.09 (s, 2H), 7.28 (br, 2H), 7.36 (t, J=7.8 Hz, 1H), 7.41 (d,J=8.7 Hz, 1H), 7.46 (d, J=7.8 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H), 7.95 (d,J=8.4 Hz, 1H), 8.09 (s, 1H), 8.16 (dd, J=1.2, 3.6 Hz, 1H), 8.94 (br,2H), 9.50 (br, 1H), 9.58 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−201.56; LCMS: purity: 98.40%; MS (m/e): 431.15 (M-42).

III-127:N2-(3-aminosulfonyl-4-methyl)phenyl-N4-[4-(N-carbamoyl-N-propyl)aminomethyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.90 (t, J=7.2 Hz, 3H), 1.66 (q, J=7.5 Hz, 2H), 2.52(s, 3H), 2.82 (m, 2H), 4.09 (s, 2H), 7.24 (d, J=8.7 Hz, 1H), 7.27 (br,2H), 7.47 (d, J=8.7 Hz, 2H), 7.87 (d, J=8.7 Hz, 3H), 8.04 (s, 1H), 8.16(d, J=3.6 Hz, 1H), 9.02 (br, 2H), 9.65 (br, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.58; LCMS: purity: 96.79%; MS (m/e): 445.20 (M-42).

III-35:N2-(4-aminosulfonyl)phenyl-N4-(4-ethylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.03 (t, J=7.5 Hz, 3H), 2.15 (q, J=7.5 Hz, 2H), 4.24(d, J=6.3 Hz, 2H), 7.13 (br, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.7Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 8.13 (d, J=3.6Hz, 1H), 8.26 (t, J=6.3 Hz, 1H), 9.41 (br, 1H), 9.58 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ −201.68; LCMS: purity: 84.18%; MS (m/e): 445.55(MH+).

III-36:N2-(3-aminosulfonyl)phenyl-N4-(4-ethylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.03 (t, J=7.5 Hz, 3H), 2.14 (q, J=7.5 Hz, 2H), 4.22(d, J=6.0 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.25 (br, 2H), 7.34 (m, 2H),7.72 (d, J=8.4 Hz, 2H), 7.95 (dt, J=2.1, 7.8 Hz, 1H), 8.09 (s, 1H), 8.10(d, J=3.6 Hz, 1H), 8.23 (t, J=6.0 Hz, 1H), 9.36 (br, 1H), 9.49 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.05; LCMS: purity: 90.32%; MS (m/e):445.17 (MH+).

III-37:N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(4-ethylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.03 (t, J=7.5 Hz, 3H), 2.14 (q, J=7.5 Hz, 2H), 2.49(s, 3H), 4.22 (d, J=6.3 Hz, 2H), 7.16 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.7Hz, 2H), 7.22 (br, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.89 (dd, J=2.1, 7.8 Hz,1H), 8.06 (d, J=3.6 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 8.23 (t, J=6.0 Hz,1H), 9.32 (br, 1H), 9.38 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−202.60; LCMS: purity: 88.90%; MS (m/e): 459.62 (MH+).

III-113:N4-(3-aminocarbonylaminomethyl)phenyl-N2-(4-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.18 (s, 2H), 6.49 (br, 1H), 7.02 (d, J=7.5 Hz, 1H),7.14 (br, 2H), 7.30 (t, J=7.8 Hz, 1H), 7.59 (br, 2H), 7.63 (d, J=9.3 Hz,2H), 7.77 (d, J=9.0 Hz, 2H), 8.18 (d, J=3.9 Hz, 1H), 9.70 (br, 1H), 9.77(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −200.91; LCMS: purity: 89.57%;MS (m/e): 432.18 (MH+).

III-114:N4-(3-aminocarbonylaminomethyl)phenyl-N2-(3-aminosulfonyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 4.16 (s, 2H), 6.47 (br, 1H), 6.98 (d, J=7.5 Hz, 1H),7.28 (m, 3H), 7.40 (m, 2H), 7.63 (m, 2H), 7.92 (m, 1H), 7.99 (s, 1H),8.17 (d, J=4.2 Hz, 1H), 9.78 (br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−200.79; LCMS: purity: 97.93%; MS (m/e): 432.14 (MH+).

III-115:N4-(3-aminocarbonylaminomethyl)phenyl-N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 2.49 (s, 3H), 4.17 (d, J=6.6 Hz, 2H), 5.53 (br, 2H),6.43 (t, 1H), 6.94 (d, J=7.8 Hz, 1H), 7.23 (m, 4H), 7.68 (m, 2H), 7.90(dd, J=6.0 Hz, 1H), 8.07 (d, J=3.6 Hz, 1H), 8.11 (d, 1H), 9.34 (br, 1H),9.36 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.31; LCMS: purity:86.53%; MS (m/e): 446.55 (MH+).

III-38:N2-(4-aminosulfonyl)phenyl-N4-(3-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.64-0.70 (m, 4H), 1.61 (m, 1H), 4.28 (d, J=6.0 Hz,2H), 7.02 (d, J=6.9 Hz, 1H), 7.13 (br, 2H), 7.31 (t, J=7.8 Hz, 1H), 7.60(d, J=8.1 Hz, 2H), 7.64 (m, 2H), 7.77 (d, J=8.7 Hz, 2H), 8.18 (d, J=3.9Hz, 1H), 8.57 (t, J=6.0 Hz, 1H), 9.69 (br, 1H), 9.73 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ −200.90; LCMS: purity: 98.26%; MS (m/e): 457.49(MH+).

III-39:N2-(3-aminosulfonyl)phenyl-N4-(3-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.64-0.71 (m, 4H), 1.61 (m, 1H), 4.27 (d, J=5.7 Hz,2H), 6.97 (d, J=7.2 Hz, 1H), 7.29 (m, 3H), 7.38 (m, 2H), 7.64 (s, 1H),7.70 (d, J=9.0 Hz, 1H), 7.93 (d, J=6.9 Hz, 1H), 8.01 (s, 1H), 8.16 (d,J=3.9 Hz, 1H), 8.55 (t, J=6.0 Hz, 1H), 9.67 (br, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −200.98; LCMS: purity: 93.15%; MS (m/e): 457.13 (MH+).

III-40:N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(3-cyclopropylcarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.64-0.70 (m, 4H), 1.61 (m, 1H), 2.48 (s, 3H), 4.26(d, J=5.7 Hz, 2H), 6.98 (d, J=8.1 Hz, 1H), 7.26 (m, 4H), 7.62 (s, 1H),7.68 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 8.13 (d,J=4.2 Hz, 1H), 8.54 (t, 1H), 9.60 (br, 1H), 9.70 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −201.36; LCMS: purity: 98.87%; MS (m/e): 471.61 (MH+).

III-122:N2-(4-aminosulfonyl)phenyl-N4-[4-(2-ethylaminocarbonylamino)ethyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.97 (t, J=7.2 Hz, 3H), 2.67 (t, J=7.2 Hz, 2H), 2.98(q, J=7.2 Hz, 2H), 3.22 (t, J=7.8 Hz, 2H), 7.16 (br, 2H), 7.17 (d, J=8.4Hz, 2H), 7.62 (d, J=9.0 Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.78 (d, J=9.3Hz, 2H), 8.14 (d, J=3.9 Hz, 1H), 9.50 (br, 1H), 9.67 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ −201.40; LCMS: purity: 98.96%; MS (m/e): 474.56(MH+).

III-123:N2-(3-aminosulfonyl)phenyl-N4-[4-(2-ethylaminocarbonylamino)ethyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.97 (t, J=7.2 Hz, 3H), 2.64 (t, J=7.2 Hz, 2H), 2.98(t, J=6.0 Hz, 2H), 3.16 (m, 2H), 7.14 (d, J=8.1 Hz, 2H), 7.25 (br, 2H),7.36 (m, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.95 (d, J=6.6 Hz, 1H), 8.09 (d,J=3.3 Hz, 2H), 9.32 (br, 1H), 9.49 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆):δ −202.04; LCMS: purity: 96.25%; MS (m/e): 474.55 (MH+).

III-124:N2-(3-aminosulfonyl-4-methyl)phenyl-N4-[4-(2-ethylaminocarbonylamino)ethyl]phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.96 (t, J=7.2 Hz, 3H), 2.51 (s, 3H), 2.64 (t, J=7.2Hz, 2H), 2.98 (q, J=7.2 Hz, 2H), 3.20 (t, J=7.5 Hz, 2H), 7.15 (d, J=8.1Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.26 (br, 2H), 7.66 (d, J=8.1 Hz, 2H),7.82 (d, J=8.1 Hz, 1H), 8.01 (s, 1H), 8.12 (d, J=4.2 Hz, 1H), 9.67 (br,2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.42; LCMS: purity: 90.25%; MS(m/e): 488.16 (MH+).

III-116:N2-(4-aminosulfonyl)phenyl-N4-(3-ethylaminocarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.97 (t, J=7.2 Hz, 3H), 3.01 (p, J=6.6 Hz, 2H), 4.20(d, J=6.0 Hz, 2H), 5.90 (t, J=5.4 Hz, 1H), 6.31 (t, J=6.0 Hz, 1H), 6.98(d, J=8.1 Hz, 1H), 7.12 (br, 2H), 7.28 (t, J=7.5 Hz, 1H), 7.63 (d, J=8.7Hz, 4H), 7.80 (d, J=8.7 Hz, 2H), 8.14 (d, J=3.6 Hz, 1H), 9.47 (br, 1H),9.58 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −201.50; LCMS: purity:84.70%; MS (m/e): 460.19 (MH+).

III-117:N2-(3-aminosulfonyl)phenyl-N4-(3-ethylaminocarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.97 (t, J=7.2 Hz, 3H), 3.02 (q, J=7.2 Hz, 2H), 4.18(s, 2H), 6.32 (br, 1H), 6.96 (d, J=7.5 Hz, 1H), 7.29 (m, 3H), 7.39 (m,2H), 7.65 (m, 2H), 7.93 (d, J=6.9 Hz, 1H), 8.02 (s, 1H), 8.16 (d, J=4.2Hz, 1H), 9.70 (br, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −200.97; LCMS:purity: 94.77%; MS (m/e): 460.13 (MH+).

III-118:N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(3-ethylaminocarbonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.98 (t, J=7.2 Hz, 3H), 2.50 (s, 3H), 3.02 (p, J=6.6Hz, 2H), 4.19 (d, J=6.0 Hz, 2H), 5.86 (t, J=5.7 Hz, 1H), 6.26 (t, J=5.7Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.22 (br, 2H),7.26 (d, J=7.8 Hz, 1H), 7.69 (m, 2H), 7.90 (dd, J=2.7, 8.7 Hz, 1H), 8.07(d, J=3.6 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 9.33 (br, 1H), 9.34 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −202.30; LCMS: purity: 98.09%; MS (m/e):474.15 (MH+).

VII-13:N2-(4-aminosulfonyl)phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.22 (t, J=7.5 Hz, 3H), 2.86 (t, 2H), 3.13 (q, J=7.5Hz, 2H), 3.50 (t, J=6.0 Hz, 2H), 4.40 (s, 2H), 7.13 (br, 2H), 7.15 (m,1H), 7.57 (m, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 8.14(d, J=3.3 Hz, 1H), 9.40 (br, 1H), 9.61 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.54; LCMS: purity: 94.58%; MS (m/e): 507.37 (MH+).

VII-14:N2-(3-aminosulfonyl)phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.22 (t, J=7.2 Hz, 3H), 2.86 (t, 2H), 3.13 (q, J=7.5Hz, 2H), 3.49 (t, 2H), 4.38 (s, 2H), 7.12 (d, J=9.0 Hz, 1H), 7.26 (br,2H), 7.36 (d, J=8.7 Hz, 1H), 7.60 (m, 2H), 7.96 (d, 1H), 8.05 (s, 1H),8.10 (d, J=3.9 Hz, 1H), 9.34 (br, 1H), 9.50 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −201.96; LCMS: purity: 82.10%; MS (m/e): 507.37 (MH+).

VII-15:N2-(3-aminosulfonyl-4-methyl)phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 1.22 (t, J=7.2 Hz, 3H), 2.85 (t, 2H), 3.13 (q, J=7.2Hz, 2H), 3.50 (t, J=5.7 Hz, 2H), 4.38 (s, 2H), 7.12 (d, J=8.1 Hz, 1H),7.16 (d, J=8.7 Hz, 1H), 7.24 (br, 2H), 7.59 (m, 2H), 7.89 (d, J=8.1 Hz,1H), 8.07 (m, 2H), 9.30 (br, 1H), 9.39 (br, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −202.55; LCMS: purity: 97.17%; MS (m/e): 521.14 (MH+).

III-23:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanoethylene-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.198 (s, 1H), 8.984 (s, 1H), 8.015 (bs, 2H),7.722-7.695 (d, J=8.1 Hz, 1H), 7.259 (s, 1H), 7.179 (s, 2H), 7.126 (s,1H), 7.098 (s, 1H), 6.965-6.938 (d, J=8.1 Hz, 1H), 2.865-2.792 (m, 4H),2.438 (s, 3H), 2.171 (s, 3H), LCMS: 441.11 (MH+).

III-24:N2-(3-Aminosulfonylphenyl)-N4-(4-cyanoethylene-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.315 (s, 1H), 9.047 (s, 1H), 8.061-8.049 (d, J=3.6Hz, 2H), 7.985 (s, 1H), 7.805-7.778 (d, J=8.1 Hz, 1H), 7.259-7.106 (m,6H), 2.866-2.816 (m, 4H), 2.173 (s, 3H), LCMS: 427.38 (MH+).

III-25:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-cyanoethylene-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.395 (s, 1H), 8.089 (s, 2H), 7.920-7.891 (d, J=8.7Hz, 1H), 7.503-7.476 (d, J=8.1 Hz, 1H), 7.315 (s, 1H), 7.175-7.124 (t,3H), 3.742 (s, 3H), 2.811-2.727 (m, 4H), LCMS: 457.07 (MH+).

III-26:N2-(3-Aminosulfonylphenyl)-N4-(4-cyanoethylene-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.512 (s, 1H), 9.400 (bs, 1H), 8.123-8.090 (t, 2H),7.988-7.963 (d, J=7.5 Hz, 1H), 7.500-7.472 (d, J=8.4 Hz, 1H),7.370-7.249 (m, 4H), 7.160-7.132 (d, J=8.4 Hz, 1H), 3.753 (s, 3H),2.812-2.708 (m, 4H), LCMS: 443.08 (MH+).

IX-46:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 11.120 (s, 1H), 9.541 (s, 1H), 8.194-8.183 (d, J=3.3Hz, 1H), 8.139 (s, 1H), 7.618-7.604 (d, J=4.2 Hz, 1H), 7.261-7.234 (m,3H), 6.996-6.983 (d, J=3.9 Hz, 1H), 3.773 (s, 3H), 2.527 (s, 3H), LCMS:438.36 (MH+).

IX-47:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 11.158 (s, 1H), 9.642 (s, 1H), 8.228-8.218 (d, J=3Hz, 1H), 8.128 (s, 1H), 8.020-7.996 (d, J=7.2 Hz, 1H), 7.452-7.413 (m,2H), 7.279 (s, 2H), 7.004-6.992 (d, J=3.6 Hz, 1H), 3.773 (s, 3H), LCMS:424.32 (MH+).

IX-48:N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 11.20 (bs, 1H), 9.332 (s, 1H), 8.075-8.057 (d, J=5.4Hz, 3H), 7.573-7.559 (d, J=4.2 Hz, 3H), 7.304-7.244 (t, 1H), 6.789 (s,1H), 3.740 (s, 3H), LCMS: 442.26 (MH+).

IX-49:N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 11.166 (s, 1H), 9.437 (s, 1H), 8.053 (s, 1H),7.930-7.901 (d, J=8.7 Hz, 2H), 7.692-7.664 (d, J=8.4 Hz, 2H), 7.591 (s,1H), 7.113 (s, 2H), 6.808 (s, 1H), 3.757 (s, 3H), LCMS: 423.97 (MH+).

III-28:N4-(3-Chloro-4-cyanoethylene-phenyl)-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 12.029 (s, 1H), 9.586 (s, 1H), 9.509 (s, 1H),8.149-7.137 (m, 2H), 8.041-8.012 (d, J=8.7 Hz, 1H), 7.873 (s, 1H),7.849-7.821 (d, J=8.4 Hz, 1H), 7.371-7.343 (d, J=8.4 Hz, 1H),7.252-7.225 (d, J=8.1 Hz, 1H), 2.996-2.952 (t, 2H), 2.843-2.797 (t, 2H),2.273-2.199 (q, 2H), 0.906-0.857 (t, 3H), LCMS: 517.38 (MH+).

III-29:N4-(3-Chloro-4-cyanoethylene-phenyl)-5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-2,4-pyrimidinediamineSodium salt

¹H NMR (DMSO-d₆): δ 9.395 (s, 1H), 9.306 (s, 1H), 8.097-8.085 (d, J=3.6Hz, 1H), 7.922-7.875 (m, 2H), 7.840 (s, 1H), 7.780-7.754 (d, J=7.8 Hz,1H), 7.375-7.347 (d, J=8.4 Hz, 1H), 6.997-6.970 (d, J=8.1 Hz, 1H),2.991-2.945 (t, 2H), 2.837-2.788 (t, 2H), 2.421 (s, 3H), 1.938-1.863 (q,2H), 0.873-0.824 (t, 3H), LCMS: 514.83 (MH+).

VII-73:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(2-hydroxy-4-methylquinolin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 11.527 (s, 1H), 9.460 (s, 1H), 9.356 (s, 1H), 8.077(s, 2H), 8.030-8.010 (d, J=6.0 Hz, 1H), 7.889 (s, 1H), 7.850 (s, 1H),7.297-7.268 (d, J=8.7 Hz, 1H), 7.219 (s, 2H), 7.076-7.048 (d, J=8.4 Hz,1H), 6.382 (s, 1H), 3.146 (s, 3H), 2.339 (s, 2H), 2.076 (s, 1H), LCMS:454.92 (MH+).

VII-74:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(2-hydroxy-4-methylquinolin-6-yl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 11.531 (s, 1H), 9.502 (s, 1H), 9.468 (s, 1H),8.117-7.900 (m, 3H), 7.303-7.243 (m, 3H), 3.150 (s, 3H), 2.352 (s, 2H),2.074 (s, 1H), LCMS: 440.94 (MH+).

III-30:N4-(4-Cyanoethylene-3-trifluoromethylphenyl)-5-fluoro-N2-(4-methyl-3-aminosulfonylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.647 (s, 1H), 9.506 (s, 1H), 8.345-8.319 (d, J=7.8Hz, 1H), 8.152-8.141 (d, J=3.3 Hz, 1H), 8.065 (s, 1H), 7.941 (s, 1H),7.891-7.864 (d, J=8.1 Hz, 1H), 7.541-7.513 (d, J=8.4 Hz, 1H), 7.244 (s,2H), 7.193-7.166 (d, J=8.1 Hz, 1H), 3.044-2.998 (t, 2H), 2.883-2.836 (t,2H), LCMS: 495.62 (MH+).

III-31:N4-(4-Cyanoethylene-3-trifluoromethylphenyl)-5-fluoro-N2-(3-aminosulfonylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.603 (s, 1H), 8.341-8.313 (d, J=8.4 Hz, 1H),8.175-8.164 (d, J=3.3 Hz, 1H), 8.059 (s, 1H), 7.948 (s, 2H), 7.546-7.517(d, J=8.7 Hz, 1H), 7.385-7.348 (m, 2H), 3.044-2.996 (t, 2H), 2.882-2.834(t, 2H), LCMS: 481.55 (MH+).

III-47:N4-[4-(2-Aminocarboxylethylene)phenyl]-5-fluoro-N2-(4-methyl-3-aminosulfonylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.374 (s, 1H), 9.258 (s, 1H), 8.115 (s, 1H),8.056-8.044 (d, J=3.6 Hz, 1H), 7.909-7.881 (d, J=8.4 Hz, 1H),7.699-7.670 (d, J=8.7 Hz, 2H), 7.269-7.128 (m, 6H), 6.740 (s, 1H),2.799-2.748 (t, 2H), 2.370-2.319 (t, 2H), LCMS: 445.11 (MH+).

III-48:N4-[4-(2-Aminocarboxylethylene)phenyl]-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.486 (s, 1H), 9.301 (s, 1H), 8.094 (bs, 2H),7.969-7.942 (d, J=8.1 Hz, 2H), 7.374-7.341 (m, 2H), 7.248 (bs, 3H),7.164-7.137 (d, J=8.1 Hz, 2H), 6.743 (s, 1H), 2.800-2.750 (t, 2H),2.370-2.321 (t, 2H), LCMS: 431.10 (MH+).

III-49:N4-[4-(2-Aminocarboxylethylene)phenyl]-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.594 (s, 1H), 9.372 (s, 1H), 8.125-8.112 (d, J=3.9Hz, 1H), 7.818 (s, 1H), 7.788 (s, 1H), 7.627-7.591 (m, 4H), 7.283 (s,1H), 7.191-7.163 (d, J=8.4 Hz, 2H), 6.735 (s, 1H), 2.821-2.773 (t, 2H),2.391-2.342 (t, 2H), LCMS: 431.05 (MH+).

VII-21:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3,4-dihydro-(1H)-quinolin-2-one-6-yl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.981 (s, 1H), 9.306 (s, 1H), 8.042-8.017 (m, 2H),7.898-7.869 (d, J=8.7 Hz, 1H), 7.565-7.515 (m, 2H), 7.148-7.120 (d,J=8.4 Hz, 2H), 6.817-6.789 (d, J=8.4 Hz, 2H), 2.863-2.814 (t, 2H), LCMS:443.05 (MH+).

VII-75:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(2-N,N′-dimethylamine-quinolin-6-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.393 (s, 2H), 8.270 (s, 1H), 8.081 (bs, 2H),7.944-7.903 (m, 2H), 7.789-7.781 (d, J=2.4 Hz, 1H), 7.508-7.478 (d, J=9Hz, 1H), 7.124-7.065 (m, 3H), 3.146 (s, 6H), LCMS: 467.99 (MH+).

VII-76:N2-(3-Aminosulfonylphenyl)-N4-(2-N,N′-dimethylamine-quinolin-6-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.518 (s, 1H), 9.446 (s, 1H), 8.266 (s, 1H),8.118-8.017 (m, 3H), 7.953-7.921 (d, J=9.6 Hz, 1H), 7.82-7.76 (m, 2H),7.516-7.485 (d, J=9.3 Hz, 1H) 7.331 (s, 2H), 7.265 (s, 2H), 7.099-7.068(d, J=9.3 Hz, 1H), 3.147 (s, 6H).

III-51:N2-(3-Aminosulfonylphenyl)-N4-[(1-ethylpyrazolyl-5-aminocarbonylmethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.50 (s, 1H,), 9.38 (s, 1H), 8.10 (s, 2H), 7.93 (bs,2H), 7.75 (d, 2H, J=8.4 Hz), 7.50 (s, 1H), 7.36 (m, 5H), 6.15 (s, 1H),3.98 (d, 2H, J=7.8 Hz), 3.66 (s, 2H), 1.24 (s, 3H): LCMS: purity: 99%;MS (m/e): 511 (MH⁺).

III-52:N2-(3-Aminosulfonyl-4-methylphenyl)-5-N4-[(1-ethylpyrazolyl-5-aminocarbonylmethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.39 (s, 1H), 9.34 (s, 1H), 8.10 (d, 2H, J=10.8 Hz),7.93 (d, 2H), 7.75 (d, 2H, J=7.8 Hz), 7.29 (m, 4H), 6.15 (s, 1H), 3.98(d, 2H, J=6.9 Hz), 3.66 (s, 2H), 2.45 (s, 3H), 1.26 (t, 3H, J=6.3 Hz):LCMS: purity: 87%; MS (m/e): 525 (MH⁺).

III-50:N2-(3-Aminosulfonylphenyl)-5-fluoro-N-4-[4(1-methylpyrazolyl-3-aminocarbonylmethylene)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.09 (s, 2H), 7.96 (d, 1H, J=6.6 Hz), 7.69 (d, 2H,J=8.1 Hz), 7.49 (s, 1H), 7.31 (m, 4H), 6.39 (s, 1H), 3.72 (s, 3H), 3.56(s, 2H): LCMS: purity: 92%; MS (m/e): 497 (MH⁺).

IV-12:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(N-methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.40 (d, 1H, J=7.8 Hz), 8.15 (d, 1H, J=3.6 Hz), 8.09(s, 1H), 7.96 (s, 1H), 7.84 (m, 1H), 7.55 (t, 1H, J=7.8 Hz), 7.44 (d,2H), 7.21 (m, 3H), 2.45 (s, 3H), 2.43 (s, 3H): LCMS: purity: 99%; MS(m/e): 467 (MH⁺).

IV-9:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(N,N-dimethylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.75 (s, 1H), 9.57 (s, 1H), 8.56 (bs, 1H), 8.19 (s,1H, J=2.7 Hz), 8.10 (s, 1H), 7.89 (m, 2H), 7.62 (m, 3H), 7.38 (s, 3H),7.27 (s, 1H), 2.62 (s, 6H): LCMS: purity: 98%; MS (m/e): 467 (MH⁺).

IV-10:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(N,N-dimethylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.71 (s, 1H), 9.46 (s, 1H), 8.59 (d, 1H, J=8.4 Hz),8.16 (d, 1H, J=3.6 Hz), 8.11 (d, 1H, J=2.4 Hz), 7.85 (m, 2H), 7.58 (t,1H, J=8.1 Hz), 7.39 (d, 1H, 8.7 Hz), 7.21 (m, 3H), 2.62 (s, 6H), 2.48(s, 3H): LCMS: purity: 99%; MS (m/e): 481 (MH⁺).

IV-11:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(N-methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.73 (s, 1H), 9.53 (σ, 1H), 8.40 (d, 1H, J=8.7 Hz),8.19 (s, 1H), 8.09 (s, 1H), 7.96 (m, 2H), 7.56 (m, 1H), 7.40 (m, 4H),7.27 (s, 2H), 2.43 (s, 3H): LCMS: purity: 99%; MS (m/e): 453 (MH⁺).

VI-34:N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-5-fluoro-N4-(4-trifluoromethylphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.53 (s, 1H), 9.36 (s, 1H), 8.13 (d, 1H, J=3.6 Hz),7.90 (d, 2H, J=9 Hz), 7.80 (s, 2H), 7.30 (d, 2H, J=8.7 Hz), 7.03 (s,2H), 3.76 (s, 3H), 2.21 (s, 3H); LCMS: purity: 92%; MS (m/e): 488 (MH⁺).

VI-35:N2-(3-Aminosulfonylphenyl)-N4-(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.47 (s, 1H), 9.32 (s, 1H), 8.09 (m, 2H), 7.94 (bd,1H, J=6.9 Hz), 7.69 (d, 2H, J=9 Hz), 7.33 (m, 4H), 7.25 (s, 2H), 1.28(s, 9H); LCMS: purity: 98%; MS (m/e): 416 (MH⁺)

VI-36:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.35 (s, 1H), 9.28 (s, 1H), 8.11 (bs, 1H), 8.04 (d,1H, J=3.3 Hz), 7.86 (bdd, 1H, J=8.1 Hz), 7.67 (d, 2H, J=8.4 Hz), 7.33(d, 2H, J=8.4 Hz), 7.21 (bs, 2H), 7.12 (m, 1H), 2.38 (s, 3H), 1.22 (s,9H); LCMS: purity: 99%; MS (m/e): 430 (MH⁺).

VI-37:N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.28 (bs, 2H), 8.05 (d, 1H, J=3.9 Hz), 7.86 (d, 1H,J=2.4 Hz), 7.75 (bd, 1H), 7.64 (d, 2H, J=8.7 Hz), 7.33 (d, 2H, J=8.7Hz), 7.01 (s, 2H), 3.75 (s, 3H), 3.31 (s, 3H), 1.27 (s, 9H); LCMS:purity: 96%; MS (m/e): 460 (MH⁺).

VI-38:N2-(3-Aminosulfonylphenyl)-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.78 (s, 1H), 8.36 (bdd, 1H, J=9 Hz), 8.21 (bd, 1H,J=2.1 Hz), 8.10 (d, 1H, J=2.1 Hz), 8.07 (s, 1H), 7.89 (bd, 1H, J=6.9Hz), 7.62 (d, 1H, J=9.3 Hz), 7.38 (m, 2H), 7.27 (m, 2H); LCMS: purity:99%; MS (m/e): 463 (MH⁺).

VI-39:N2-(3-Aminosulfonyl-4-methyl-phenyl)-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.74 (s, 1H), 9.51 (s, 1H), 8.38 (bd, 1H, J=8.7 Hz),8.17 (d, 1H, J=2.4 Hz), 8.10 (s, 1H), 8.08 (s, 1H), 7.83 (d, 1H, J=8.1Hz), 7.61 (d, 1H, J=8.7 Hz), 7.25 (s, 2H), 7.18 (d, 1H, J=8.1 Hz), 7.09(s, 1H), 2.50 (s, 3H); LCMS: purity: 96%; MS (m/e): 477 (MH⁺).

VI-40:N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(4-chloro-3-trifluoromethyl-phenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.74 (s, 1H), 9.42 (s, 1H), 8.38 (bd, 1H, J=9 Hz),8.17 (d, 1H, J=1.8 Hz), 8.08 (s, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 7.61(d, 1H, J=9 Hz), 7.04 (s, 2H), 3.77 (s, 3H), 2.21 (s, 1H); LCMS: purity:93%; MS (m/e): 507 (MH⁺).

VI-41:N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-(4-trifluorophenyl)-2,4-pyrimidinediamine

LCMS: purity: 96%; MS (m/e): 463 (MH⁺).

VI-42:N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-(4-trifluoromethoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.66 (s, 1H), 9.60 (s, 1H), 8.27 (d, 1H, J=1.8 Hz),8.15 (bdd, 1H, J=2.7 Hz), 8.00 (bdd, 1H, J=1.5 and 9.0 Hz), 7.91 (d, 2H,J=8.1 Hz), 7.47 (s, 2H), 7.41 (d, 1H, J=8.7 Hz), 7.32 (d, 2H, J=8.7 Hz);LCMS: purity: 95%; MS (m/e): 478 (M⁺).

IX-21:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(2-cyanobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 91%; MS (m/e): 460 (MH⁺).

VI-43:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.57 (s, 1H), 9.35 (s, 1H), 8.27 (d, 1H, J=2.7 Hz),8.09 (d, 1H, J=3.6 Hz), 8.00 (dd, 1H, J=2.7 and 8.7 Hz), 7.66 (d, 2H,J=8.4 Hz), 7.44 (s, 2H), 7.36 (m, 3H), 1.22 (s, 9H); LCMS: purity: 94%;MS (m/e): 451 (MH⁺).

VI-44:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(3-chloro-4-trifluoromethyl-phenyl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 87%; MS (m/e): 497 (MH⁺).

III-62:N2-(3-Aminosulfonylphenyl)-N4-(4-benzylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.53 (s, 1H), 9.36 (s, 1H), 8.10 (d, 1H, J=2.7 Hz),8.02 (bs, 1H), 7.96 (bs, 1H), 7.83 (d, 1H, J=1.8 Hz), 7.69 (bdd, 1H,J=9.3 Hz), 7.47-7.31 (m, 9H), 7.26 (s, 1H), 7.18 (d, 1H, J=9 Hz); LCMS:purity: 96%; MS (m/e): 450 (M⁺).

III-63:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-benzylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.42 (s, 1H), 9.33 (s, 1H), 8.05 (m, 2H), 7.87 (m,2H), 7.70 (bd, 1H, J=8.7 Hz), 7.46-7.14 (m, 10H), 5.19 (s, 2H), 2.45 (s,3H); LCMS: purity: 99%; MS (m/e): 465 (MH⁺).

III-64:N2-(3-Aminosulfonyl-4-chlorophenyl)-N4-(4-benzylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.65 (s, 1H), 9.40 (s, 1H), 8.22 (d, 1H, J=2.1 Hz),8.10 (d, 1H, J=3.6 Hz), 8.02 (dd, 1H, J=2.7 and 9 Hz), 7.81 (d, 1H,J=2.4 Hz), 7.70 (dd, 1H, J=2.7 and 9 Hz), 7.39 (m, 8H), 7.19 (d, 2H, J=9Hz), 5.20 (s, 2H); LCMS: purity: 99%; MS (m/e): 485 (MH⁺).

III-65:N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(4-benzylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.37 (s, 2H), 8.08 (bs, 1H), 7.77 (m, 2H), 7.71 (bd,1H, J=8.7 Hz), 7.37 (m, 5H), 7.18 (m, 2H), 7.03 (s, 2H), 5.18 (s, 2H),3.75 (s, 3H), 2.16 (s, 3H); LCMS: purity: 94%; MS (m/e): 495 (MH⁺).

VI-45:N2-(3-Aminosulfonyl-4-iso-propylphenyl)-N4-(3-chloro-4-methoxy-phenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 10.25 (s, 2H), 8.25 (d, 1H, J=8.4 Hz), 7.79 (m, 2H),7.74 (d, 1H, J=1.8 Hz), 7.57) dd, 1H, J=1.8 and 8.7 Hz), 7.45 (m, 3H),7.12 (d, 1H, J=8.7 Hz), 3.83 (s, 3H), 3.77 (m, 1H), 1.19 (d, 6H, J=6.9Hz); LCMS: purity: 95%; MS (m/e): 467 (MH⁺).

RIX-22:N2-(3-Aminosulfonyl-4-iso-propylphenyl)-N4-(2-cyanobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.53 (s, 1H), 9.41 (s, 1H), 8.29 (d, 1H, J=1.8 Hz),8.10 (d, 1H, J=3.6 Hz), 8.03 (d, 1H, J=2.4 Hz), 8.01 (d, 1H), 7.90 (d,1H), 7.87 (d, 1H, J=2.1 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.32 (m, 3H), 3.75(m, 1H), 1.20 (d, 6H, J=6.6 Hz); LCMS: purity: 95%; MS (m/e): 467 (MH⁺).

I-8:N2-(3-Aminosulfonyl-4-iso-propylphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.71 (bs, 2H), 8.11 (d, 1H, J=4.2 Hz), 7.95 (d, 1H,J=2.1 Hz), 7.82 (dd, 1H, J=2.1 and 8.4 Hz), 7.71 (d, 2H, J=8.7 Hz), 7.40(d, 1H, J=8.4 Hz), 7.36 (s, 2H), 7.03 (d, 2H, J=9.3 Hz), 5.25 (s, 2H),3.75 (m, 1H), 1.19 (d, 6H, J=6.9 Hz); LCMS: purity: 99%; MS (m/e): 457(MH⁺).

N4-(4-Aminosulfonylmethylenephenyl)-N2-(3-aminosulfonyl-4-methyl-phenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.43 (s, 1H), 9.41 (s, 1H), 8.09 (m, 2H), 7.92 (dd,1H, J=2.4 and 8.4 Hz), 7.82 (d, 2H, J=8.4 Hz), 7.29 (d, 2H, J=8.4 Hz),7.22 (s, 2H), 7.19 (d, 1H, J=7.2 Hz), 6.80 (s, 2H), 4.23 (s, 2H), 2.21(s, 3H); LCMS: purity: 99%; MS (m/e): 468 (MH⁺).

VI-46:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-(4-trifluoromethylmethyleneoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 10.26 (bs, 2H), 8.24 (d, 1H, J=8.1 Hz), 7.87 (s,1H), 7.70 (bd, 1H, J=8.1 Hz), 7.60 (d, 2H, J=9 Hz), 7.34 (bs, 2H), 7.25(d, 1H, J=8.1 Hz), 7.04 (d, 2H, J=9 Hz), 4.75 (q, 2H, J=8.7 Hz); LCMS:purity: 98%; MS (m/e): 472 (MH⁺).

VI-47:N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-trifluoromethylmethyleneoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 10.20 (s, 1H), 10.09 (s, 1H), 8.23 (d, 1H, J=4.8Hz), 7.89 (s, 1H), 7.84 (m, 1H), 7.62 (d, 2H, J=8.7 Hz), 7.45 (m, 2H),7.34 (bs, 2H), 7.03 (d, 2H, J=8.7 Hz), 4.75 (q, 2H, J=9 Hz); LCMS:purity: 98%; MS (m/e): 458 (MH⁺).

VI-48:N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-(4-trifluoromethylmethyleneoxyphenyl)-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 10.23 (s, 1H), 10.03 (s, 1H), 8.23 (d, 1H, J=4.5Hz), 8.10 (d, 1H, J=2.1 Hz), 7.87 (dd, 1H, J=2.4 and 9 Hz), 7.62 (d, 2H,J=8.7 Hz), 7.54 (bs, 2H), 7.47 (d, 1H, J=9 Hz), 7.05 (d, 2H, J=8.7 Hz),4.75 (q, 2H, J=6 Hz); LCMS: purity: 98%; MS (m/e): 492 (M⁺).

V-16:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(2-cyanoethylene-benzothiophen-5-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.423 (s, 2H), 8.305 (s, 1H), 8.096-8.070 (m, 2H),7.938-7.903 (d, J=8.4 Hz, 1H), 7.846-7.818 (d, J=8.4 Hz, 1H),7.670-7.634 (d, J=8.7 Hz, 1H), 7.233-7.217 (m, 3H), 7.154-7.127 (d,J=8.1 Hz, 1H), 3.238-3.192 (t, 2H), 2.974-2.928 (t, 3H), 2.065 (s, 3H),LCMS: 482.90 (MH+).

IX-45:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[(4R)-1-(2-cyanoacetyl)-pyrrolidin-4-yl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.324 (s, 1H), 8.540 (s, 1H), 7.904-7.891 (d, J=3.9Hz, 1H), 7.670-7.650 (d, J=6 Hz, 1H), 7.579-7.557 (d, J=6.6 Hz, 1H),7.185 (s, 1H), 7.158 (s, 1H), 4.673 (bs, 1H), 3.705 (bs, 1H),3.552-3.457 (m, 2H), 3.371-3.355 (m, 1H), 2.186 (bs, 1H), 2.032-1.979(m, 1H), LCMS: 434.42 (MH+).

VI-113: N2,N4-Bis-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.75 (s, 1H), 9.52 (s, 1H), 8.20 (m, 2H), 8.11 (d,2H, J=7.2 Hz), 7.94 (d, 1H, J=8.1 Hz), 7.52 (m, 2H), 7.41 (m, 4H), 7.27(s, 2H): LCMS: purity: 94%; MS (m/e): 440 (MH⁺).

VI-114:N2,N4-Bis-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.61 (s, 1H), 9.33 (s, 1H), 8.23 (d, 2H, J=2.1 Hz),8.11 (d, 2H, J=1.8 Hz), 8.02 (m, 1H), 7.88 (m, 1H), 7.40 (s, 2H), 7.31(d, 1H, J=8.4 Hz), 7.24 (s, 2H), 7.21 (d, 1H, J=8.4 Hz), 2.55 (s, 6H):LCMS: purity: 89%; MS (m/e): 468 (MH⁺).

VI-115:N2,N4-Bis-(3-aminosulfonyl-4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.86 (s, 1H), 9.64 (s, 1H), 8.34 (d, 1H, J=2.7 Hz),8.28 (d, 1H, J=3.0 Hz), 8.24 (d, 1H, J=2.7 Hz), 8.20 (d, 1H, J=3.6 Hz),8.01 (m, 1H), 7.63 (s, 1H), 7.57 (d, 1H, J=8.7 Hz), 7.49 (s, 1H), 7.46(s, 1H): LCMS: purity: 91%; MS (m/e): 508 (MH⁺).

IX-17:N2-[3-Aminosulfonyl-4-(4-methylpiperazine-1-yl)phenyl]-N4-(3-cyanomethylene-1H-indol-6-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 94%; MS (m/e): 537 (MH⁺).

IX-18:N2-[3-Aminosulfonyl-4-(4-methylpiperazine-1-yl)phenyl]-N4-(3-cyanomethylene-1H-indol-7-yl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 96%; MS (m/e): 537 (MH⁺).

VI-116:N2-[3-Aminosulfonyl-4-(4-methylpiperazine-1-yl)phenyl]-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 92%; MS (m/e): 523 (MH⁺).

IX-19:N4-(3-cyanomethylene-1H-indol-5-yl)-5-fluoro-N2-[3-(1-methyl-4-aminopiperadine)sulfonyl-4-methylphenyl]-2,4-pyrimidinediamine

LCMS: purity: 97%; MS (m/e): 549 (MH⁺).

I-78:N2-(3-Aminosulfonylphenyl)-N4-[4-(N-cyanoacetyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine.

¹H NMR (DMSO-d6): δ 8.10 (s, 2H), 7.95 (s, 1H), 7.80 (s, 2H), 7.55 (s,2H), 7.34 (s, 1H), 7.26 (s, 1H), 3.88 (s, 2H): LCMS: purity: 96%; MS(m/e): 442 (MH⁺).

I-79:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(N-cyanoacetyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.11 (s, 1H), 8.06 (s, 1H), 7.78 (d, 1H, J=8.7 Hz),7.50 (d, 2H, J=8.7 Hz), 7.17 (m, 3H), 3.88 (s, 2H): LCMS: purity: 91%;MS (m/e): 456 (MH⁺).

I-80:N2-(3-Aminosulfonylphenyl)-5-fluoroN4-[3-methyl-4-(N-cyanoacetyl)aminophenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.11 (d, 1H, J=3.6 Hz), 8.03 (s, 1H), 7.98 (d, 1H,J=6.6 Hz), 7.58 (s, 2H), 7.35 (d, 2H, J=9.0 Hz), 7.26 (s, 1H), 3.91 (s,2H), 2.19 (s, 3H): LCMS: purity: 92%; MS (m/e): 456 (MH⁺).

I-81:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoroN4-[3-methyl4-(N-cyanoacetyl)aminophenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.07 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.23 (m,5H), 3.90 (s, 2H), 2.49 (s, 3H), 2.18 (s, 3H): LCMS: purity: 98%; MS(m/e): 470 (MH⁺).

I-82:N2-(3-Aminosulfonylphenyl)-N4-[3-chloro-4-(N-cyanoacetyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.17 (d, 1H, J=3.6 Hz), 8.06 (s, 1H), 7.96 (d, 1H,J=5.4 Hz), 7.85 (d, 1H, J=8.7 Hz)), 7.59 (s, 1H), 7.40 (s, 1H), 7.36 (d,1H, J=8.1 Hz), 7.26 (s, 1H), 3.97 (s, 2H): LCMS: purity: 97%; MS (m/e):476 (MH⁺).

I-83:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-chloro-4-(N-cyanoacetyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.13 (d, 1H, J=3.3), 7.89 (d, 1H, J=2.1) 7.85 (m,1H), 7.59 (d, 1H, J=9.0 Hz), 7.21 (m, 2H), 3.97 (s, 2H), 2.49 s, 3H):LCMS: purity: 90%; MS (m/e): 490 (MH⁺).

I-84:N2-(3-Aminosulfonylphenyl)-5-fluoroN4-[3-methoxy-4-(N-cyanoacetyl)aminophenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.55 (s, 1H), 0.50 (s, 1H), 9.39 (s, 1H), 8.11 (s,1H) 7.98 (d, 1H, J=7.2 Hz), 7.81 (d, 1H, J=8.4 Hz), 7.53 (d, 1H, J=9.3Hz), 7.41 (s, 1H), 7.34 (s, 2H), 7.25 (s, 1H), 3.96 (s, 2H), 3.78 (s,3H): LCMS: purity: 93%; MS (m/e): 472 (MH⁺).

I-85:N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoroN4-[3-methoxy-4-(N-cyanoacetyl)aminophenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 9.55 (s, 1H), 9.39 (s, 1H), 9.35 (s, 1H), 8.08 (t,3H, J=2.4) 7.92 (d, 1H, J=8.1 Hz), 7.81 (d, 1H, J=8.7 Hz), 7.53 (d, 1H,J=9.6 Hz), 7.41 (s, 1H), 7.23 (s, 2H), 7.17 (d, 1H, J=7.8 Hz), 3.96 (s,2H), 3.77 (s, 3H), 2.49 (s, 3H): LCMS: purity: 93%; MS (m/e): 486 (MH⁺).

I-86:N2-(3-Aminosulfonylphenyl)-N4-[4-(N-cyanoacetyl-N-methyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.17 (d, 1H, J=3.6 Hz)), 8.13 (s, 1H), 7.92 (t, 3H,J=8.1 Hz), 7.40 (m, 4H), 3.59 (s, 2H), 3.17 (s, 3H): LCMS: purity: 96%;MS (m/e): 457 (MH⁺).

I-87:N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(N-cyanoacetyl-N-methyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d6): δ 8.12 (s, 2H), 7.94 (d, 2H, J=8.7 Hz), 7.86 (d, 1H,J=6.0 Hz), 7.31 (d, 2H, J=9.0 Hz), 7.28 (d, 3H, J=8.4 Hz), 3.60 (s, 2H),3.17 (s, 3H), 2.49 (s, 3H): LCMS: purity: 93%; MS (m/e): 471 (MH⁺).

Example 41 Assay for Ramos B-Cell Line Stimulated with IL-4

B-cells stimulated with cytokine Interleukin-4 (IL-4) activate theJAK/Stat pathway through phosphorylation of the JAK family kinases,JAK-1 and JAK-3, which in turn phosphorylate and activate thetranscription factor Stat-6. One of the genes upregulated by activatedStat-6 is the low affinity IgE receptor, CD23. To study the effect ofinhibitors on the JAK family kinases, human Ramos B cells are stimulatedwith human IL-4.

The Ramos B-cell line was acquired from ATCC (ATCC Catalog No.CRL-1596). The cells were cultured in RPMI 1640 (Cellgro, MediaTech,Inc., Herndon, Va., Cat No. 10-040-CM) with 10% fetal bovine serum(FBS), heat inactivated (JRH Biosciences, Inc, Lenexa, Kans., Cat No.12106-500M) according to ATCC propagation protocol. Cells weremaintained at a density of 3.5×10⁵. The day before the experiment, RamosB-cells were diluted to 3.5×10⁵ cells/mL to ensure that they were in alogarithmic growth phase.

Cells were spun down and suspended in RPMI with 5% serum. 5×10⁴ cellswere used per point in a 96-well tissue culture plate. Cells werepre-incubated with compound or DMSO (Sigma-Aldrich, St. Louis, Mo., CatNo. D2650) vehicle control for 1 hour in a 37° C. incubator. Cells werethen stimulated with IL-4 (Peprotech Inc., Rocky Hill, N.J., Cat No.200-04) for a final concentration of 50 units/mL for 20-24 hours. Cellswere then spun down and stained with anti-CD23-PE(BD Pharmingen, SanDiego, Calif., Cat No. 555711) and analyzed by FACS. Detection wasperformed using a BD LSR I System Flow Cytometer, purchased from BectonDickinson Biosciences of San Jose, Calif. The IC₅₀ calculated based onthe results of this assay are provided in TABLE XII.

Example 42 Primary Human T-Cell Proliferation Assay Stimulated with IL-2

Primary human T-cells derived from peripheral blood and pre-activatedthrough stimulation of the T-cell receptor and CD28, proliferate invitro in response to the cytokine Interleukin-2 (IL-2). Thisproliferative response is dependent on the activation of JAK-1 and JAK-3tyrosine kinases, which phosphorylate and activate the transcriptionfactor Stat-5.

Human primary T cells were prepared as follows. Whole blood was obtainedfrom a healthy volunteer, mixed 1:1 with PBS, layered on to FicollHypaque (Amersham Pharmacia Biotech, Piscataway, N.J., Catalog#17-1440-03) in 2:1 blood/PBS:ficoll ratio and centrifuged for 30 min at4° C. at 1750 rpm. The lymphocytes at the serum: ficoll interface wererecovered and washed twice with 5 volumes of PBS. The cells wereresuspended in Yssel's medium (Gemini Bio-products, Woodland, Calif.,Catalog #400-103) containing 40 U/mL recombinant IL2 (R and D Systems,Minneapolis, Minn., Catalog #202-IL (20 rig)) and seeded into a flaskpre-coated with 1 μg/mL anti-CD3 (BD Pharmingen, San Diego, Calif.,Catalog #555336) and 5 μg/mL anti-CD28 (Immunotech, Beckman Coulter ofBrea Calif., Catalog #IM1376). The primary T-cells were stimulated for3-4 days, then transferred to a fresh flask and maintained in RPMI with10% FBS and 40 U/mL IL-2.

Primary T-cells were washed twice with PBS to remove the IL-2 andresuspended in Yssel's medium at 2×10⁶ cells/mL. 50 μL of cellsuspension containing 80 U/mL IL-2 was added to each well of a flatbottom 96 well black plate. For the unstimulated control, IL-2 wasomitted from the last column on the plate. Compounds were seriallydiluted in dimethyl sulfoxide (DMSO, 99.7% pure, cell culture tested,Sigma-Aldrich, St. Louis, Mo., Catalog No. D2650) from 5 mM in 3-folddilutions, and then diluted 1:250 in Yssel's medium. 50 μL of 2×compound was added per well in duplicate and the cells were allowed toproliferate for 72 hours at 37° C.

Proliferation was measured using CellTiter-Glo® Luminescent CellViability Assay (Promega), which determines the number of viable cellsin culture based on quantitation of the ATP present, as an indicator ofmetabolically active cells. The substrate was thawed and allowed to cometo room temperature. After mixing the Cell Titer-Glo reagent and diluenttogether, 100 μL was added to each well. The plates were mixed on anorbital shaker for two minutes to induce lysis and incubated at roomtemperature for an additional ten minutes to allow the signal toequilibrate. Detection was performed using a Wallac Victor2 1420multilabel counter purchased from Perkin Elmer, Shelton, Conn. The IC₅₀calculated based on the results of this assay are provided in TABLE XII.

Example 43 A549 Epithelial Line Stimulated with IFNγ

A549 lung epithelial cells up-regulate ICAM-1 (CD54) surface expressionin response to a variety of different stimuli. Therefore, using ICAM-1expression as readout, compound effects on different signaling pathwayscan be assessed in the same cell type. IFNγ up-regulates ICAM-1 throughactivation of the JAK/Stat pathway. In this example, the up-regulationof ICAM-1 by IFNγ was assessed.

The A549 lung epithelial carcinoma cell line originated from theAmerican Type Culture Collection. Routine culturing was with F12K media(Mediatech Inc., Lenexa, Kans., Cat. No. 10-025-CV) with 10% fetalbovine serum, 100 I.U. penicillin and 100 ng/mL streptomycin (completeF12k media). Cells were incubated in a humidified atmosphere of 5% CO₂at 37° C. Prior to use in the assay, A549 cells were washed with PBS andtrypsinized (Mediatech Inc., Cat. No. 25-052-CI) to lift the cells. Thetrypsin cell suspension was neutralized with complete F12K media andcentrifuged to pellet the cells. The cell pellet was resuspended incomplete F12K media at a concentration of 2.0×10⁵/mL. Cells were seededat 20,000 per well, 100 μL total volume, in a flat bottom tissue cultureplate and allowed to adhere overnight.

On day two, A549 cells were pre-incubated with a 2,4-substitutedpyrimidinediamine test compound or DMSO (control) (Sigma-Aldrich, St.Louis, Mo., Catalog No. D2650) for 1 hour. The cells were thenstimulated with IFNγ (75 ng/mL) (Peprotech Inc., Rocky Hill, N.J., Cat.No. 300-02) and allowed to incubate for 24 hours. The final testcompound dose range was 30 μM to 14 nM in 200 μL F12K media containing5% FBS, 0.3% DMSO.

On day three, the cell media was removed and the cells were washed with200 μL PBS (phosphate buffered saline). Each well was trypsinized todissociate the cells, then neutralized by addition of 200 μL completeF12K media. Cells were pelleted and stained with an APC conjugated mouseanti-human ICAM-1 (CD54) (BD Pharmingen, San Diego, Calif., Catalog#559771) antibody for 20 minutes at 4° C. Cells were washed with icecold FACS buffer (PBS+2% FBS) and surface ICAM-1 expression was analyzedby flow cytometry. Detection was performed using a BD LSR I System FlowCytometer, purchased from BD Biosciences of San Jose, Calif. Events weregated for live scatter and the geometric mean was calculated(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Geometric means were plotted against the compound concentration togenerate a dose response curve. The IC₅₀ calculated based on the resultsof this assay are provided in TABLE XII.

Example 44 U937 IFNγ ICAM1 FACS Assay

U937 human monocytic cells up-regulate ICAM-1 (CD54) surface expressionin response to a variety of different stimuli. Therefore, using ICAM-1expression as readout, compound effects on different signaling pathwayscan be assessed in the same cell type. IFNγup-regulates ICAM-1 throughactivation of the JAK/Stat pathway. In this example, the up-regulationof ICAM-1 by IFNγ was assessed.

The U937 human monocytic cell line was obtained from ATCC of RockvilleMd., catalog number CRL-1593.2, and cultured in RPM1-1640 mediumcontaining 10% (v/v) FCS. U937 cells were grown in 10% RPMI. The cellswere then plated at a concentration of 100,000 cells per 160 μL in 96well flat bottom plates. The test compounds were then diluted asfollows: 10 mM test compound was diluted 1:5 in DMSO (3 μL 10 mM testcompound in 12 μL DMSO), followed by a 1:3 serial dilution of testcompound in DMSO (6 μL test compound serially diluted into 12 μL DMSO togive 3-fold dilutions). Then 4 μL of test compound was transferred to 76μL of 10% RPMI resulting in a 10× solution (100 μM test compound, 5%DMSO). For control wells, 4 μL of DMSO was diluted into 76 μL 10% RPMI.

The assay was performed in duplicate with 8 points (8 3-fold dilutionconcentrations from 10 μl) and with 4 wells of DMSO only (control wells)under stimulated conditions and 4 wells of DMSO only under unstimulatedconditions.

The diluted compound plate was mixed 2× using a multimek (BeckmanCoulter of Brea, Calif.) and then 20 μL of the diluted compounds wastransferred to the 96 well plate containing 160 μL of cells, which werethen mixed again twice at low speeds. The cells and compounds were thenpre-incubated for 30 minutes at 37° C. with 5% CO₂.

The 10× stimulation mix was made by preparing a 100 ng/mL solution ofhuman IFNγ in 10% RPMI. The cells and compound were then stimulated with20 μL of IFNγ stimulation mix to give a final concentration of 10 ng/mLIFNγ, 10 μM test compound, and 0.5% DMSO. The cells were kept underconditions for stimulation for 18-24 hours at 37° C. with 5% CO₂.

The cells were transferred to a 96 well round bottom plate for stainingand then kept on ice for the duration of the staining procedure. Cellswere spun down at 1000 rpm for 5 minutes at 4° C., following which thesupernatant was removed. Following removal of the supernatant, 1 μL APCconjugated mouse anti-human ICAM-1 antibody was added per 100 μL FACSbuffer. The cells were then incubated on ice in the dark for 30 minutes.Following incubation, 150 μL of FACS buffer was added and the cells werecentrifuged at 1000 rpm for 5 minutes at 4° C., following which thesupernatant was removed. After removal of the supernatant, 200 μL ofFACS buffer was added and the cells were resuspended. After suspension,the cells were centrifuged at 1000 rpm for 5 min at 4° C. Supernatantwas then removed prior to resuspension of the cells in 150 μL FACSbuffer.

Detection was performed using a BD LSR I System Flow Cytometer,purchased from BD Biosciences of San Jose, Calif. The live cells weregated for live scatter and the geometric mean of ICAM-APC was measured(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Both % live cells and ICAM-1 expression was analyzed. The assays for thetest compounds were carried out in parallel with a control compound ofknown activity. The EC₅₀ for the control compound is typically 40-100nM. The IC₅₀ calculated based on the results of this assay are providedin TABLE XII.

TABLE XII Example Example Example Example Compound 41 42 43 44 I-10.36551 9.89222 18.4509 35.3335 I-2 0.53194 I-3 0.10738 0.98708 9999 I-40.04905 0.17843 4.85721 I-5 1.64619 29.901 I-6 0.52212 20.9805 9999 I-70.12002 0.50172 I-8 0.0587 0.1743 9999 0.41 I-9 0.23306 0.48494 15.63340.78723 I-10 0.02551 0.09568 6.54622 0.26124 I-11 0.02333 0.0392917.6237 0.3294 I-12 0.03694 0.05968 3.19514 0.22195 I-13 0.00627 0.005051.34069 0.0435 I-14 0.01296 0.01149 0.61167 0.04176 I-15 0.30896 1.183184.96519 I-16 0.12424 0.4356 7777 I-17 0.0487 0.04318 2.34513 0.36534I-18 0.28251 1.48925 8888 2505.23 I-19 0.50856 1.04177 24.8675 10.0825I-20 0.03672 0.06619 6.53867 0.33882 I-21 0.09302 0.25767 22.7159 0.8223I-22 0.23636 0.94439 14.3679 4.43304 I-23 0.03013 0.08823 9999 0.45476I-24 0.05422 0.29639 9999 1.04466 I-25 0.05582 1.6129 25.3098 8888 I-260.03781 0.40073 4.23449 0.42446 I-27 0.06186 0.91443 3.48033 0.53438I-28 0.06454 0.5598 7777 1.89233 I-29 0.1196 0.50183 I-30 5.433333.57085 I-31 4.62505 I-32 0.16136 2.78095 5.49713 1.96749 I-33 0.09650.1705 8888 0.89708 I-34 0.06229 0.80566 7777 1.05493 I-35 0.046961.1331 8.58425 1.82151 I-36 8.80466 9999 I-37 0.49851 3.68499 5.73717I-38 6.44228 I-39 0.84081 9.32297 I-40 0.30838 31.0382 3345.23 I-410.03738 10.15 I-42 0.02408 8888 I-43 0.01826 0.18317 36.6502 0.77073I-44 0.05316 0.34166 9999 5.06833 I-45 0.1036 0.83377 17.0422 3.63512I-46 0.11322 0.40872 9999 0.75129 I-47 0.12011 0.55068 0.75908 I-481.40357 I-49 2.31794 5.55983 I-50 0.37337 25.1264 I-51 0.26268 2.1171532.1941 I-52 0.15228 5.30087 9999 68.6571 I-53 0.23595 12.2055 I-540.27682 7.15982 I-55 9999 I-56 0.10355 0.2618 4.97271 0.42424 I-570.02161 0.05314 9999 0.13971 I-58 0.00505 0.01925 0.73026 0.06599 I-590.00655 0.02487 0.94741 0.05766 I-60 0.10288 2.17439 7.89243 0.84765I-61 0.04586 0.12299 8888 0.42748 I-62 0.10056 0.37599 3.52859 0.73487I-63 0.16924 1.31421 34.3138 0.69103 I-64 0.11281 1.87772 5.166071.15237 I-65 0.09651 0.04731 8888 0.31629 I-66 0.10306 0.28704 99990.68933 I-67 0.03322 0.15663 4.61611 0.23869 I-68 0.18704 0.482434.96049 0.91274 I-69 0.11784 1.02837 5.64408 5000.08 I-70 0.061380.57305 3.43038 0.384 I-71 0.06178 0.13591 3.26769 0.32803 I-72 0.052390.30295 3.30881 0.57377 I-73 0.11976 0.7281 5.55843 1.06264 I-74 0.244751.49815 10.7945 1.75731 I-75 0.19865 3.3 7777 3.1 I-76 0.10102 0.195855.13601 1.12224 I-77 0.14716 1.61795 I-78 0.6349 1.2051 I-79 0.46061.0611 I-80 0.3649 0.4697 I-81 0.3597 0.9566 I-82 0.2439 1.3819 I-830.158 1.7561 14.9 I-84 1.4005 I-85 0.7913 I-86 0.9162 I-87 1.0381 I-881.07518 I-89 5.49992 9999 I-90 0.40109 2.19063 6.16341 I-91 2.03142 I-920.16624 0.54302 9999 15.59 I-93 0.26489 1.17393 23.774 11.0701 I-940.34492 0.56287 5.66845 I-95 0.11825 0.32508 9999 6.3 I-96 0.131770.77151 40.8692 3.30063 I-97 0.21244 0.86883 31.0729 27.4081 I-980.29451 37.2587 10.9783 I-99 0.06863 0.14752 9999 3.77549 I-100 0.380279999 6670.09 I-101 0.32832 51.1576 36.6028 I-102 0.21893 0.21079 43.766315.5943 I-103 1.24843 9999 I-104 1.42542 9999 I-105 1.1675 9999 I-1062.95316 I-107 1.51103 I-108 0.14545 0.14758 9999 3.97385 I-109 0.305270.20336 25.9633 9.93933 I-110 0.35788 0.25307 20.584 3.92933 I-1110.89035 9999 I-112 2.36464 9999 I-113 0.16466 1.6854 9999 13.5121 I-1140.44754 6.70638 9999 9999 I-115 0.79259 7777 I-116 0.27394 0.97166 99994455.33 I-117 0.35266 0.30095 36.4268 14.5685 I-118 0.292 0.557232.42563 I-119 0.21095 2.43898 9.67128 11.8985 I-120 0.20071 0.2796419.9754 4.45634 I-121 0.18382 0.63384 14.5419 2.98512 I-122 0.29151 3.59999 15.6681 I-123 0.15927 0.22497 12.8283 2.2221 I-124 0.10241 0.3419910.373 1.33026 I-125 0.53802 I-126 0.35476 0.60989 7.20132 I-127 0.23330.50965 2.5105 I-128 0.87135 I-129 0.61228 I-130 0.60114 1.73251 I-1310.26226 3.78086 2.99277 I-132 0.35129 0.46431 2.71959 I-133 0.236561.34872 9999 I-134 0.17762 0.50998 9999 3.23999 I-135 0.11208 0.104183.24251 1.82933 I-136 0.13205 0.19642 8.11382 1.64002 I-137 0.386721.09918 9999 29.5795 I-138 0.4607 0.22286 91.4861 9.46799 I-139 0.374660.24038 11.5578 3.26019 I-140 0.38751 I-141 0.1625 0.66903 15.6032 I-1420.15485 0.85438 9999 I-143 1.19256 I-144 1.00541 I-145 0.54156 0.3493I-146 0.36436 7777 9999 I-147 0.07985 0.17442 7777 9999 I-148 0.061170.24003 9999 9999 I-149 0.1613 0.19724 14.7293 I-150 0.06569 0.068067777 10.5387 I-151 0.06185 0.07829 9999 8888 I-152 0.30174 1.5412 I-1530.11405 0.33375 9999 I-154 0.27631 0.9925 9999 I-155 0.11775 0.099329999 65.0584 I-156 0.06549 0.14151 9999 2.62254 I-157 0.24574 1.89069999 I-158 0.2967 0.44535 1.38012 I-159 0.33805 0.53944 1.63449 I-1600.13042 0.2484 0.92282 I-161 0.31398 2.41123 I-162 0.05105 0.13566 99990.59381 I-163 0.17656 0.4391 1.40511 I-164 9999 I-165 0.24517 0.446441.63555 I-166 0.61646 I-167 0.14175 7777 I-168 0.15437 1.17511 9999I-169 0.0546 0.1373 8888 I-170 0.4507 I-171 0.11717 0.41497 I-1720.04734 0.2771 38.674 1.09663 I-173 0.11513 0.907 9999 15.5343 I-1740.11681 1.23383 8888 I-175 0.14696 3.0806 9999 I-176 0.25875 1.69038I-177 8888 0.5 I-178 0.0235 0.0293 0.11756 I-179 0.02427 0.01178 0.11711I-180 0.0624 0.02868 0.4558 I-181 0.01301 I-182 0.18961 1.12876 8888I-183 0.24913 1.83159 2.27747 I-184 0.48571 2.57372 6.62465 I-1850.29773 9999 I-186 0.18828 1.08437 3.53394 I-187 2.91228 I-188 0.04270.0642 15.0825 0.50022 I-189 0.13708 0.14331 6.74171 0.50811 I-1900.14533 0.24207 9.30992 1.5006 I-191 0.13487 0.29228 0.79644 I-1920.13748 0.15499 0.97787 I-193 0.03822 0.05562 9999 I-194 0.02858 0.099355.02722 I-195 0.08263 0.12705 9999 9999 I-196 0.12446 0.13926 99990.75397 I-197 0.13477 0.32885 1.2782 I-198 0.10154 0.46016 9999 0.80536I-199 0.23967 3.02692 2.68752 I-200 9999 I-201 9999 I-202 3.075 I-2030.26472 0.68359 5.77164 3.1332 I-204 0.25571 1.6463 3.92821 I-2050.31543 1.8632 9.4856 3341.09 I-206 0.72572 I-207 8888 I-208 1.39961I-209 0.58003 4.46766 2.96679 9999 I-210 0.86614 I-211 1.05253 I-2120.75778 I-213 11.4811 I-214 0.14442 1.32831 1.30455 I-215 0.97626 I-2160.20482 0.49337 1.56836 I-217 0.02498 0.21692 36.591 0.4785 I-2180.07262 0.11588 3.26785 0.43399 I-219 0.03162 0.12305 7.16246 0.58776I-220 0.12138 1.06662 7777 8888 I-221 0.34372 2.68161 4.43571 I-2220.03308 0.58244 9999 0.84 I-223 0.08803 0.62525 9.08836 1.20989 I-2240.03615 0.19417 11.324 0.4936 I-225 0.69987 I-226 0.49797 I-227 1.48242I-228 3.80514 I-229 3.75639 I-230 0.08426 0.06925 10.477 0.46548 I-2310.09468 0.29003 9999 8.40421 I-232 1.42979 I-233 0.14834 0.37693 99991.74874 I-234 0.10247 1.00762 8.15676 2.01923 I-235 0.17818 0.4695 99992.55555 I-236 1.98037 I-237 0.14699 2.04005 9999 3.57746 I-238 0.164770.45567 9999 1.12717 I-239 0.23965 9999 7.05758 I-240 0.20499 5.259228888 I-241 0.26564 0.44243 2.87423 I-242 0.52009 I-243 0.91747 I-2440.28501 1.40668 14.7078 3.11959 I-245 0.20153 1.74332 16.6871 4.1888I-246 0.10624 0.18232 8.87569 0.87257 I-247 0.225 0.1187 11.115 1.0767I-248 0.38838 0.13774 2.65851 I-249 0.51223 11.0003 I-250 0.67255 I-2510.16719 0.15516 34.8518 1.09204 I-252 0.0906 0.55777 74.2104 2.46619I-253 0.12662 2.56423 I-254 0.15452 1.91498 8.95614 1.82459 I-2550.25614 2.86397 39.3342 5.52062 I-256 0.28206 38.2034 9999 15.9307 I-2570.14527 0.10222 3.07682 0.95888 I-258 0.02798 0.05539 9999 0.3241 I-2590.02793 0.06575 7.50745 0.3147 I-260 0.09477 0.22271 8.44012 0.98515I-261 5031.28 I-262 0.07832 0.16396 3.67509 1.04486 I-263 0.123680.06443 0.66548 I-264 0.59917 14.9995 I-265 0.04232 0.0397 4.083820.41479 I-266 0.08513 0.20071 9999 0.824 I-267 0.32828 2.01965 5.06578I-268 0.06074 0.13983 5.0785 0.21895 I-269 0.91657 I-270 0.77962 I-2719999 I-272 0.78775 I-273 0.47773 0.19296 12.8791 5.10428 I-274 1.17189I-275 0.22313 0.57744 9999 1.9 I-276 0.13508 0.10582 8.0902 0.8217 I-2770.15065 0.09153 6.91127 1.47355 I-278 0.19343 0.41215 11.0338 2.26901I-279 0.12274 0.16744 9999 0.9178 I-280 0.14472 0.9783 1.45628 I-2810.09321 0.09036 9999 0.97459 I-282 0.33926 0.69745 3.10495 I-283 0.518210.3617 2.94063 I-284 0.13587 0.42105 1.54787 I-285 0.13257 0.31358 1.485II-1 0.18176 1.13989 8.32597 II-2 0.24439 1.51926 4.59317 II-3 0.084040.91766 11.921 6.50431 II-4 0.31643 2.37109 3.51083 II-5 2.20619 II-60.11067 1.2178 6.38785 II-7 0.14372 0.52156 1.62567 II-8 0.03878 0.564149999 II-9 0.23159 1.31747 2.7171 II-10 0.36923 0.8756 1.39632 II-110.10669 0.19762 0.91162 II-12 0.05626 0.40891 5.52004 1.19102 II-130.32334 II-14 0.04685 0.57852 II-15 0.98189 1.10065 II-16 18.30483.71528 II-17 21.2024 8.20964 II-18 2.04279 3.30797 II-19 0.39546 88889999 II-20 0.42846 0.96892 11.5294 II-21 0.69755 1.76163 41.7481 II-220.85847 7.48812 III-1 0.15102 0.54475 1.11685 III-2 0.22374 3.435346.71592 III-3 0.53624 III-4 0.01872 0.17102 8.36734 1.71666 III-5 4.97739999 III-6 0.78109 30.674 III-7 0.0851 0.19544 12.3228 1.08953 III-80.13823 0.92083 14.4636 2.2522 III-9 0.21457 1.80396 23.6063 6.98319III-10 0.22461 0.92188 9999 3.52348 III-11 0.0642 0.04604 2.244050.16825 III-12 0.07001 0.10746 3.51838 0.32092 III-13 0.2953 0.70092III-14 0.13985 0.05263 3.60147 0.58483 III-15 0.07596 0.10691 4.655210.55294 III-16 0.2733 0.34222 7.23576 1.79675 III-17 0.05674 0.19740.78205 III-18 0.03659 0.13567 0.54387 III-19 0.07229 0.17392 21.88990.05559 III-20 0.04299 0.76298 6.63588 3.33323 III-21 0.0303 0.113780.33867 III-22 0.04545 0.07611 8888 0.44428 III-23 0.39727 III-240.25751 1.62056 III-25 0.27162 1.25963 III-26 0.16196 0.58276 III-270.05834 0.11898 7777 0.25737 III-28 3.74795 17.4221 III-29 3.6333312.3622 9999 III-30 0.06455 0.31911 9999 III-31 0.09536 0.32762 1.70465III-32 4.40366 3.31651 9999 III-33 1.68071 0.85213 III-34 0.472760.38085 III-35 1.0814 III-36 0.3944 0.3819 III-37 0.2997 0.834 III-380.1976 1.127 III-39 0.1171 0.1297 4.15 1.435 III-40 0.1341 0.2286 1.116III-41 1.0134 III-42 0.2936 0.6406 III-43 0.2705 0.8975 III-44 1.43012III-45 0.29277 0.38431 III-46 0.21144 1.05234 III-47 0.21084 0.366429999 III-48 0.20373 0.21773 9999 III-49 0.17801 III-50 0.30572 1.96867III-51 1.00749 III-52 0.18299 1.20459 III-53 0.0977 0.28629 1.13155III-54 0.13522 0.13989 9999 1.59326 III-55 0.14436 0.97312 III-560.19581 0.49929 III-57 0.05356 0.16996 55.5368 0.83776 III-58 0.156711.25684 III-59 0.14965 0.45792 III-60 0.13462 0.17751 25.5295 1.01469III-61 0.25873 1.08295 III-62 0.1715 0.699 III-63 0.3153 1.8768 III-640.4473 5.9565 III-65 0.209 0.9359 III-66 0.14152 1.15034 0.96668 III-670.34745 3.05467 III-68 3.23069 III-69 3.31825 III-70 0.06446 0.169219999 1.64984 III-71 0.09785 0.36848 8.25586 1.70255 III-72 1.95167III-73 0.13087 0.43435 III-74 0.09524 0.17541 9999 0.93514 III-750.16969 0.22009 10.0944 1.77125 III-76 0.1042 0.1348 0.447 III-77 0.17740.2095 0.681 III-78 0.2754 0.2041 7777 22.9 III-79 0.16853 0.96749III-80 3.15582 0.84435 III-81 0.18003 0.20392 48.3461 3.42825 III-820.12695 0.15998 24.1674 2.27381 III-83 0.09874 0.09622 9999 1.35976III-84 0.4428 1.8956 III-85 0.07272 0.12242 9999 3.62044 III-86 0.09760.09394 9999 6.44528 III-87 0.14099 0.14172 76.2393 2.94666 III-880.14065 0.16557 10.6231 2.03999 III-89 0.11498 III-90 0.35751 0.468222.6323 III-91 0.14274 0.46742 III-92 0.32272 1.89757 III-93 0.173080.81891 III-94 0.16161 0.71606 III-95 0.1494 0.37003 29.7109 III-963.32588 2.18995 III-97 0.27887 1.02568 III-98 0.11654 0.45747 III-991.03465 2.17142 III-100 0.16233 0.19656 1.9107 III-101 0.2401 0.4464III-102 0.30171 0.48559 III-103 0.23001 1.05998 2.42638 III-104 0.241731.19132 2.1621 III-105 1.27754 III-106 0.04277 0.07508 5.89649 0.49188III-107 0.21914 0.5404 1.52384 III-108 0.18343 1.21503 1.50897 III-1090.14312 0.25198 0.53111 III-110 0.24698 0.99788 13.5631 III-111 0.321210.92557 5.34359 III-112 2.47605 III-113 1.0305 0.345 III-114 2.6833III-115 1.6524 III-116 0.19663 3.94714 7777 III-117 0.39696 III-1180.62434 2.29421 III-119 1.29867 III-120 0.65536 0.5542 III-121 0.574951.0202 III-122 0.53873 III-123 0.17252 1.38789 III-124 0.29523 III-1250.8356 III-126 0.1972 0.4701 III-127 0.1982 0.6123 III-128 0.145130.13942 28.0649 1.43941 III-129 0.17355 0.1799 31.2977 1.187 IV-10.07356 0.28652 0.27169 IV-2 0.08002 0.36242 0.70488 IV-3 0.09325 IV-40.15095 0.3032 2.42396 IV-5 0.09767 0.11589 16.0697 0.50367 IV-6 0.102920.13159 0.88048 IV-7 0.11241 0.20304 1.23784 IV-8 0.16592 0.62672 IV-90.19023 1 IV-10 0.13472 0.71395 IV-11 0.3672 IV-12 0.25666 1.21823 V-12.00456 9.77279 9999 V-2 1.17796 V-3 0.66409 13.7306 V-4 0.10843 1.539339.24355 V-5 0.69624 V-6 0.02185 0.07083 7777 0.57206 V-7 0.05877 0.127035.00173 0.82053 V-8 0.02908 0.22532 5.20729 0.61971 V-9 1.11064 V-100.26102 8.26777 2.69871 V-11 0.0698 0.79519 8888 1.41593 V-12 0.188170.95693 54.0071 3.03787 V-13 0.05289 0.46847 6.86738 1.19717 V-140.19711 2.59168 6.84803 V-15 0.17289 9.30756 8888 V-16 8.3722 VI-10.20474 VI-2 0.08925 3.57169 9999 VI-3 0.20565 8.79279 9999 9999 VI-40.02107 0.2312 9999 9999 VI-5 0.04047 0.71837 8888 1.3851 VI-6 0.037471.44938 14.9708 7.70441 VI-7 0.76592 VI-8 2.28135 VI-9 0.05327 0.944539.95895 14.5216 VI-10 0.22022 2.39519 24.9026 9999 VI-11 0.25923 4.6173547.0634 7.13718 VI-12 0.14575 1.3099 9999 8888 VI-13 0.09654 1.348678.2263 1.3926 VI-14 0.41325 7777 9.26616 VI-15 0.045 0.46887 0.76722VI-16 0.25935 3.91458 8888 VI-17 0.04344 0.2436 6.42231 0.45391 VI-180.25733 4.36513 6.06278 VI-19 1.02551 VI-20 0.72602 VI-21 11.321 VI-220.66268 VI-23 0.59672 VI-24 8.61565 VI-25 9.91092 VI-26 0.04444 0.02891.70264 0.257 VI-27 0.07613 3.7609 0.5446 VI-28 0.75443 VI-29 0.049820.36201 8888 VI-30 0.01324 0.1702 9999 VI-31 18.2541 VI-32 0.333231.65819 VI-33 0.27207 0.66049 VI-34 0.1567 0.8386 VI-35 0.1583 1.2589VI-36 0.3743 4.4975 VI-37 0.0692 1.0785 12.4 VI-38 0.4143 2.0675 VI-390.401 3.139 VI-40 0.2883 1.2369 VI-41 0.3425 6.2401 VI-42 0.4515 6.1678VI-43 0.7393 6.1404 VI-44 0.4293 7.3093 VI-45 0.1081 1.3279 10.53 VI-460.1435 1.2558 VI-47 0.0828 0.2589 9999 0.596 VI-48 0.3153 2.2429 VI-490.26786 1.26457 2.09896 VI-50 0.21701 0.94365 1.87806 VI-51 0.152250.54688 9999 2.13363 VI-52 0.16844 0.16223 5.91841 1.73898 VI-53 0.056310.18115 11.3381 0.56491 VI-54 0.14667 0.96651 31.0319 1.61592 VI-550.12204 0.62467 1.36955 VI-56 9.6557 VI-57 0.20172 1.18287 VI-58 0.164270.72381 9999 VI-59 0.07598 0.33972 4.98157 VI-60 0.08692 0.18673 3.845510.40964 VI-61 0.09897 0.18455 3.11335 0.36684 VI-62 3.9717 VI-63 0.159870.36325 1.74329 VI-64 5.80304 VI-65 0.09062 0.20944 4.12861 0.9643 VI-666.0949 VI-67 0.14725 0.7175 VI-68 0.1016 0.74156 26.8087 1.80963 VI-690.19376 1.34478 18.7049 VI-70 0.07056 0.31112 8888 0.65688 VI-71 1.07371VI-72 0.45477 VI-73 0.25111 2.01413 VI-74 0.09458 0.34829 9999 3.85373VI-75 0.90444 0.92854 VI-76 0.54911 0.78345 VI-77 9999 43.2745 VI-780.16137 VI-79 0.096 VI-80 0.3601 VI-81 3.1748 VI-82 0.21184 1.63499 8888VI-83 0.11255 0.29326 7.29592 0.53506 VI-84 0.13247 0.51438 4.58337VI-85 0.12862 0.76235 24.7027 VI-86 0.1531 0.17808 4.43831 0.48745 VI-870.5411 1.24269 VI-88 0.21559 1.18558 24.6776 VI-89 0.13188 0.171395.75508 2.04395 VI-90 1.075 3.9664 VI-91 0.22118 1.23424 9999 VI-920.0835 0.10732 12.9834 1.1583 VI-93 0.10988 0.5602 VI-94 0.9442 VI-951.0032 VI-96 0.80335 VI-97 3.00715 VI-98 0.13555 0.9859 9999 9999 VI-990.06845 0.6166 9999 9999 VI-100 0.32107 0.07427 9.1817 4.89859 VI-1010.91914 VI-102 0.18285 0.13496 14.7259 2.7967 VI-103 3.07902 VI-1041.98452 VI-105 10.2998 VI-106 0.06219 1.19886 9999 9999 VI-107 0.159120.07409 8888 0.85644 VI-108 9999 VI-109 0.13553 2.86926 7777 9999 VI-1100.08364 0.34532 9999 5.46321 VI-111 0.31375 1.09272 3.43245 VI-1120.15223 0.77009 1.25566 VI-113 0.6995 VI-114 0.2095 2.2419 9999 33.19VI-115 0.8899 VI-116 0.0311 0.1742 8.101 0.673 VII-1 6.653 VII-2 36.2228VII-3 14.0844 16.5455 VII-4 2.49292 9999 VII-5 4.12527 VII-6 0.102081.99812 23.4363 3.6535 VII-7 0.50186 3.91608 9999 VII-8 0.39911 8.633357777 7777 VII-9 0.24627 2.71965 17.0751 5.34695 VII-10 0.86258 VII-110.60232 VII-12 0.60208 6.68655 31.7728 VII-13 0.13967 0.38047 77771.28577 VII-14 0.10259 0.17683 9.92695 0.87716 VII-15 0.06662 0.1205813.1417 0.56816 VII-16 0.27544 1.07422 24.3537 VII-17 0.35301 2.097656.96416 VII-18 0.22688 0.83852 1.29055 VII-19 0.08753 0.51424 12.531.25627 VII-20 0.28603 0.69758 VII-21 0.54792 VII-22 0.1114 0.1276 99990.84875 VII-23 0.12929 0.16124 61.259 0.59644 VII-24 0.62303 VII-250.21695 VII-26 0.54544 1.20006 9.26107 VII-27 0.41342 2.05177 6.2489VII-28 0.0367 0.70906 16.5843 8888 VII-29 0.0476 1.46279 30.5071 38.4779VII-30 0.0358 0.02682 8.91572 0.70135 VII-31 0.12467 0.17419 99997.27828 VII-32 0.1071 0.0321 8888 2.057 VII-33 0.02891 0.01839 VII-340.04504 0.02248 VII-35 0.0448 0.0461 8888 0.245 VII-36 0.02945 0.1190982.8107 1.08605 VII-37 0.02814 VII-38 0.06234 0.41674 VII-39 0.771570.91901 VII-40 0.23602 6.48486 9999 VII-41 0.04694 0.26426 9999 9999VII-42 0.6688 7.28447 45.547 VII-43 0.60291 9999 VII-44 0.03299 0.545529.12322 1.22643 VII-45 0.04385 0.28169 4.03246 0.47741 VII-46 0.96115VII-47 2.67352 VII-48 0.03083 0.3365 9999 0.66 VII-49 0.03778 0.054933.06481 0.57652 VII-50 0.34963 0.85602 4.41963 5.0643 VII-51 0.541091.79232 9999 VII-52 47.0815 VII-53 0.16792 0.48379 5.46124 VII-540.29487 0.59608 64.6261 VII-55 0.18411 0.59857 1.66866 VII-56 0.184951.28469 1.92946 VII-57 0.10717 0.8182 10.6982 0.73524 VII-58 0.135770.26518 1.09844 VII-59 0.83147 2.98692 VII-60 0.06501 0.15195 2.603970.56965 VII-61 3333.23 0.14031 2.69156 0.35591 VII-62 0.10412 0.144229999 0.49561 VII-63 0.23311 0.30064 6.02744 VII-64 0.36258 3.8097 VII-650.38533 3.05525 VII-66 0.36866 2.87032 VII-67 0.31467 0.76791 VII-680.81157 1.30092 VII-69 0.07673 0.69583 7.50321 0.98982 VII-70 0.065420.37513 6.47721 2.76015 VII-71 0.14944 0.56875 5.47023 VII-72 0.084840.41516 9.93038 1.18433 VII-73 6.08963 4444.5 VII-74 4.56128 8888 VII-750.54401 VII-76 0.67316 VII-77 0.12407 1.78366 3.53562 VII-78 0.085830.6825 9999 8888 VII-79 0.20627 3.20167 7777 VII-80 2.03294 VII-813.07323 VII-82 0.3126 1.07552 8888 VII-83 0.0775 0.93655 9999 VIII-11.58839 VIII-2 0.1777 0.40901 8.54969 VIII-3 0.15335 1.84224 10.0847IX-1 0.08928 0.58079 4.88106 1.13251 IX-2 0.0795 0.28213 8888 1.76728IX-3 0.11457 IX-4 0.12037 IX-5 0.02962 0.07382 6.09872 1.84617 IX-60.08403 0.53531 36.7836 8888 IX-7 0.10867 0.7509 9999 4.73418 IX-80.04643 0.12398 5.24218 0.54254 IX-9 8.87638 5016.37 IX-10 6.40728 IX-110.1146 0.21538 7777 2.23698 IX-12 0.09731 0.11725 7777 3.47525 IX-130.13847 0.43042 30.2755 1.84616 IX-14 0.05744 0.65645 3.37992 1.08814IX-15 0.21708 0.15678 7777 5.36404 IX-16 0.20966 0.22281 7777 2.50539IX-17 0.1084 0.8151 21.95 1.98 IX-18 0.1684 2.4 55.18 6.659 IX-19 0.11791.5963 3.368 IX-20 0.12232 1.79208 2.89558 IX-21 0.2709 2.7359 IX-220.2953 1.59 IX-23 9.57788 IX-24 6.33149 38.3916 IX-25 6.3071 IX-26 9999IX-27 1.37969 7.62931 IX-28 1.66076 10.0529 IX-29 3.45769 IX-30 1.935296.79992 IX-31 1.4025 IX-32 9999 9999 IX-33 0.52102 IX-34 0.58245 0.575573.95135 IX-35 0.45471 0.8665 9999 2.09598 IX-36 1.03601 9999 IX-373.70466 IX-38 2.31392 IX-39 1.39641 IX-40 9999 9999 IX-41 0.133186.25787 9999 IX-42 0.29236 2.17331 9999 IX-43 0.52347 2.80149 IX-440.22324 0.78907 8.16963 2.93981 IX-45 3.615 IX-46 0.07388 1.38897 7777IX-47 0.22282 2.38854 IX-48 0.25834 2.62415 9.56437 IX-49 0.0965 61.89549999 IX-50 0.17891 9999 IX-51 0.23983 9999 IX-52 0.11677 IX-53 0.24002IX-54 0.17434 2.47371 9999 X-1 8.24549 X-2 1.84451 X-3 0.34839 1.094444.97666 1.3837

What is claimed is:
 1. A method of treating a T-cell mediated autoimmunedisease, comprising administering to a patient suffering from such anautoimmune disease a compound having formula II, or a pharmaceuticallyacceptable salt thereof, in an amount effective to treat the autoimmunedisease

wherein: X is selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl,carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl,alkynyl and substituted alkynyl; R is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;ring A is phenyl; Y is selected from the group consisting of a bond,—NR⁷—, —C(O)NR⁷—, —NR⁷C(O), —NR⁷C(O)O—, —OC(O)NR⁷—, —NR⁷C(O)NR⁷—, oxygenand sulfur, where R⁷ is independently hydrogen, alkyl or substitutedalkyl; alk is a bond or a straight or branched chain alkylene group,wherein when alk and Y each are a bond then R¹ is attached to ring A bya single covalent bond; R¹ is selected from the group consisting ofcyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxylester, carboxyl ester oxy, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, andaminocarbonylamino; or R¹-alk-Y— is R¹⁰—C(O)—S-alk-C(O)—, wherein alk isas defined herein and R¹⁰ is alkyl or substituted alkyl; or R¹-alk-Y— isR¹¹R¹²NS(O)₂—, wherein R¹¹ and R¹² independently are alkyl orsubstituted alkyl; p is 0, 1, 2 or 3; each R² independently is selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, aryloxy, substitutedaryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, nitro, and halo; Z¹, Z², and Z³ are carbon;q is 1, 2 or 3; each R³ independently is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic andsubstituted heterocyclic; R⁴ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺ is a metalcounterion selected from the group consisting of K⁺, Na⁺, Li⁺, or⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the nitrogen of SO₂NR⁴W isN⁻, a divalent counterion selected from the group consisting of Ca²⁺,Mg²+, and Ba²⁺, and the nitrogen of SO₂NR⁴W is N⁻; and W is selectedfrom the group consisting of C₁-C₃ alkylene, substituted C₁-C₃ alkylene,C₂-C₃ alkenylene and substituted C₂-C₃ alkenylene wherein one or more ofthe carbon atoms have been replaced with a moiety selected from oxygen,sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is selected from the groupconsisting of hydrogen and alkyl or is a bond participating in a —N═C<site of unsaturation.
 2. The method of claim 1 in which the compound isadministered in combination with, or adjunctively to, a compound thatinhibits Syk kinase with an IC₅₀ in the range of at least 10 μM.
 3. Amethod of treating or preventing allograft transplant rejection in atransplant recipient, comprising administering to the transplantrecipient a compound having formula II, or a pharmaceutically acceptablesalt thereof, in an amount effective to treat or prevent the rejection

wherein: X is selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl,carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl,alkynyl and substituted alkynyl; R is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;ring A is phenyl; Y is selected from the group consisting of a bond,—NR⁷—, —C(O)NR⁷—, —NR⁷C(O), —NR⁷C(O)O—, —OC(O)NR⁷—, —NR⁷C(O)NR⁷—, oxygenand sulfur, where R⁷ is independently hydrogen, alkyl or substitutedalkyl; alk is a bond or a straight or branched chain alkylene group,wherein when alk and Y each are a bond then R¹ is attached to ring A bya single covalent bond; R¹ is selected from the group consisting ofcyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxylester, carboxyl ester oxy, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, andaminocarbonylamino; or R¹-alk-Y— is R¹⁰—C(O)—S-alk-C(O)—, wherein alk isas defined herein and R¹⁰ is alkyl or substituted alkyl; or R¹-alk-Y— isR¹¹R¹²NS(O)₂—, wherein R¹¹ and R¹² independently are alkyl orsubstituted alkyl; p is 0, 1, 2 or 3; each R² independently is selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, aryloxy, substitutedaryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, nitro, and halo; Z¹, Z², and Z³ are carbon;q is 1, 2 or 3; each R³ independently is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic andsubstituted heterocyclic; R⁴ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺ is a metalcounterion selected from the group consisting of K⁺, Na⁺, Li⁺, or⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the nitrogen of SO₂NR⁴W isN⁻, a divalent counterion selected from the group consisting of Ca²⁺,Mg²+, and Ba²⁺, and the nitrogen of SO₂NR⁴W is N⁻; and W is selectedfrom the group consisting of C₁-C₃ alkylene, substituted C₁-C₃ alkylene,C₂-C₃ alkenylene and substituted C₂-C₃ alkenylene wherein one or more ofthe carbon atoms have been replaced with a moiety selected from oxygen,sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is selected from the groupconsisting of hydrogen and alkyl or is a bond participating in a —N═C<site of unsaturation.
 4. The method of claim 3 in which the rejection isacute rejection.
 5. The method of claim 3 in which the rejection ischronic rejection.
 6. The method of claim 3 in which the rejection ismediated by HVGR or GVHR.
 7. The method of claim 3 in which theallograft transplant is selected from a kidney, a heart, a liver and alung.
 8. The method of claim 3 in which the compound is administered incombination with, or adjunctively to, another immunosuppressant.
 9. Themethod of claim 8 in which the immunosuppressant is selected fromcyclosporine, tacrolimus, sirolimus, an inhibitor of IMPDH,mycophenolate, mycophanolate mofetil, an anti-T-cell antibody and OKT3.10. A method of treating or preventing a Type IV hypersensitivityreaction, comprising administering to a subject a compound havingformula II, or a pharmaceutically acceptable salt thereof, in an amounteffective to treat or prevent the hypersensitivity reaction

wherein: X is selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl,carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl,alkynyl and substituted alkynyl; R is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;ring A is phenyl; Y is selected from the group consisting of a bond,—NR⁷—, —C(O)NR⁷—, —NR⁷C(O), —NR⁷C(O)O—, —OC(O)NR⁷—, —NR⁷C(O)NR⁷—, oxygenand sulfur, where R⁷ is independently hydrogen, alkyl or substitutedalkyl; alk is a bond or a straight or branched chain alkylene group,wherein when alk and Y each are a bond then R¹ is attached to ring A bya single covalent bond; R¹ is selected from the group consisting ofcyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxylester, carboxyl ester oxy, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, andaminocarbonylamino; or R¹-alk-Y— is R¹⁰—C(O)—S-alk-C(O)—, wherein alk isas defined herein and R¹⁰ is alkyl or substituted alkyl; or R¹-alk-Y— isR¹¹R¹²NS(O)₂—, wherein R¹¹ and R¹² independently are alkyl orsubstituted alkyl; p is 0, 1, 2 or 3; each R² independently is selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, aryloxy, substitutedaryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, nitro, and halo; Z¹, Z², and Z³ are carbon;q is 1, 2 or 3; each R³ independently is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic andsubstituted heterocyclic; R⁴ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺ is a metalcounterion selected from the group consisting of K⁺, Na⁺, Li⁺, or⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the nitrogen of SO₂NR⁴W isN⁻, a divalent counterion selected from the group consisting of Ca²⁺,Mg²+, and Ba²⁺, and the nitrogen of SO₂NR⁴W is N⁻; and W is selectedfrom the group consisting of C₁-C₃ alkylene, substituted C₁-C₃ alkylene,C₂-C₃ alkenylene and substituted C₂-C₃ alkenylene wherein one or more ofthe carbon atoms have been replaced with a moiety selected from oxygen,sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is selected from the groupconsisting of hydrogen and alkyl or is a bond participating in a —N═C<site of unsaturation.
 11. The method of claim 10 comprisingadministering the compound prophylactically.
 12. A method of inhibitinga signal transduction cascade in which JAK3 kinase plays a role,comprising contacting a cell expressing a receptor involved in such asignaling cascade with a compound having formula II, or apharmaceutically acceptable salt thereof, in an amount effective toinhibit the signal transduction cascade

wherein: X is selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl,carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl,alkynyl and substituted alkynyl; R is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;ring A is phenyl; Y is selected from the group consisting of a bond,—NR⁷—, —C(O)NR⁷—, —NR⁷C(O), —NR⁷C(O)O—, —OC(O)NR⁷—, —NR⁷C(O)NR⁷—, oxygenand sulfur, where R⁷ is independently hydrogen, alkyl or substitutedalkyl; alk is a bond or a straight or branched chain alkylene group,wherein when alk and Y each are a bond then R¹ is attached to ring A bya single covalent bond; R¹ is selected from the group consisting ofcyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxylester, carboxyl ester oxy, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, andaminocarbonylamino; or R¹-alk-Y— is R¹⁰—C(O)—S-alk-C(O)—, wherein alk isas defined herein and R¹⁰ is alkyl or substituted alkyl; or R¹-alk-Y— isR¹¹R¹²NS(O)₂—, wherein R¹¹ and R¹² independently are alkyl orsubstituted alkyl; p is 0, 1, 2 or 3; each R² independently is selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, aryloxy, substitutedaryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, nitro, and halo; Z¹, Z², and Z³ are carbon;q is 1, 2 or 3; each R³ independently is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic andsubstituted heterocyclic; R⁴ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺ is a metalcounterion selected from the group consisting of K⁺, Na⁺, Li⁺, or⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the nitrogen of SO₂NR⁴W isN⁻, a divalent counterion selected from the group consisting of Ca²⁺,Mg²+, and Ba²⁺, and the nitrogen of SO₂NR⁴W is N⁻; and W is selectedfrom the group consisting of C₁-C₃ alkylene, substituted C₁-C₃ alkylene,C₂-C₃ alkenylene and substituted C₂-C₃ alkenylene wherein one or more ofthe carbon atoms have been replaced with a moiety selected from oxygen,sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is selected from the groupconsisting of hydrogen and alkyl or is a bond participating in a —N═C<site of unsaturation.
 13. A method of treating or preventing a JAKkinase-mediated disease, comprising administering to a subject acompound having formula II, or a pharmaceutically acceptable saltthereof, in an amount effective to treat or prevent the JAKkinase-mediated disease

wherein: X is selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl,carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl,alkynyl and substituted alkynyl; R is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;ring A is phenyl; Y is selected from the group consisting of a bond,—NR⁷—, —C(O)NR⁷—, —NR⁷C(O), —NR⁷C(O)O—, —OC(O)NR⁷—, —NR⁷C(O)NR⁷—, oxygenand sulfur, where R⁷ is independently hydrogen, alkyl or substitutedalkyl; alk is a bond or a straight or branched chain alkylene group,wherein when alk and Y each are a bond then R¹ is attached to ring A bya single covalent bond; R¹ is selected from the group consisting ofcyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxylester, carboxyl ester oxy, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, andaminocarbonylamino; or R¹-alk-Y— is R¹⁰—C(O)—S-alk-C(O)—, wherein alk isas defined herein and R¹⁰ is alkyl or substituted alkyl; or R¹-alk-Y— isR¹¹R¹²NS(O)₂—, wherein R¹¹ and R¹² independently are alkyl orsubstituted alkyl; p is 0, 1, 2 or 3; each R² independently is selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, aryloxy, substitutedaryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, nitro, and halo; Z¹, Z², and Z³ are carbon;q is 1, 2 or 3; each R³ independently is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic andsubstituted heterocyclic; R⁴ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺ is a metalcounterion selected from the group consisting of K⁺, Na⁺, Li⁺, or⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the nitrogen of SO₂NR⁴W isN⁻, a divalent counterion selected from the group consisting of Ca²⁺,Mg²+, and Ba²⁺, and the nitrogen of SO₂NR⁴W is N⁻; and W is selectedfrom the group consisting of C₁-C₃ alkylene, substituted C₁-C₃ alkylene,C₂-C₃ alkenylene and substituted C₂-C₃ alkenylene wherein one or more ofthe carbon atoms have been replaced with a moiety selected from oxygen,sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is selected from the groupconsisting of hydrogen and alkyl or is a bond participating in a —N═C<site of unsaturation.
 14. The method of claim 13 in which theJAK-mediated disease is HVGR or GVHR.
 15. The method of claim 13 inwhich the JAK-mediated disease is acute allograft rejection.
 16. Themethod of claim 13 in which the JAK-mediated disease is chronicallograft rejection.
 17. A pharmaceutical formulation, comprising: acompound having formula II, or a pharmaceutically acceptable saltthereof,

wherein: X is selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl,carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl,alkynyl and substituted alkynyl; R is selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;ring A is phenyl; Y is selected from the group consisting of a bond,—NR⁷—, —C(O)NR⁷—, —NR⁷C(O), —NR⁷C(O)O—, —OC(O)NR⁷—, —NR⁷C(O)NR⁷—, oxygenand sulfur, where R⁷ is independently hydrogen, alkyl or substitutedalkyl; alk is a bond or a straight or branched chain alkylene group,wherein when alk and Y each are a bond then R¹ is attached to ring A bya single covalent bond; R¹ is selected from the group consisting ofcyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxylester, carboxyl ester oxy, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, andaminocarbonylamino; or R¹-alk-Y— is R¹⁰—C(O)—S-alk-C(O)—, wherein alk isas defined herein and R¹⁰ is alkyl or substituted alkyl; or R¹-alk-Y— isR¹¹R¹²NS(O)₂—, wherein R¹¹ and R¹² independently are alkyl orsubstituted alkyl; p is 0, 1, 2 or 3; each R² independently is selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, aryloxy, substitutedaryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, nitro, and halo; Z¹, Z², and Z³ are carbon;q is 1, 2 or 3; each R³ independently is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic andsubstituted heterocyclic; R⁴ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl and M⁺, wherein M⁺ is a metalcounterion selected from the group consisting of K⁺, Na⁺, Li⁺, or⁺N(R⁶)₄, wherein R⁶ is hydrogen or alkyl, and the nitrogen of SO₂NR⁴W isN⁻, a divalent counterion selected from the group consisting of Ca²⁺,Mg²+, and Ba²⁺, and the nitrogen of SO₂NR⁴W is N⁻; and W is selectedfrom the group consisting of C₁-C₃ alkylene, substituted C₁-C₃ alkylene,C₂-C₃ alkenylene and substituted C₂-C₃ alkenylene wherein one or more ofthe carbon atoms have been replaced with a moiety selected from oxygen,sulfur, S(O), S(O)₂, C(O), or NR⁸ where R⁸ is selected from the groupconsisting of hydrogen and alkyl or is a bond participating in a —N═C<site of unsaturation; and at least one pharmaceutically acceptableexcipient, diluent, preservative, or stabilizer, or mixtures thereof.